BRPI0609668A2 - compound, pharmaceutical composition, and use of a compound - Google Patents

Abstract

COMPOUND, PHARMACEUTICAL COMPOSITION, AND USE OF A COMPOUND. The invention relates to novel thiophene derivatives of formula (I), their preparation and their use as pharmaceutically active compounds. Said compounds particularly act as immunosuppressive agents, wherein ring A represents oxadiazole and the other substituents are as defined in the description.

Description

"COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND"

Field of the invention

The present invention relates to S1P1 / EDG1 receptor agonists of Formula (I) and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also relates to related aspects including processes for preparing the compounds, pharmaceutical compositions containing a compound of Formula (I), and their use as vascular function enhancing compounds and as immunomodulatory agents either alone or in combination with other compounds. active compounds or therapies.

Fundamentals of the invention

The human immune system is designed to defend the body against foreign microorganisms and substances that cause infection or disease. Complex regulatory mechanisms ensure that the immune response is selected against the organism or invasive substance and not against the host. In some cases, these control mechanisms are unregulated and autoimmune responses may be developed. One consequence of the uncontrolled inflammatory response is severe organ, cell, tissue or joint damage. With current treatment, the entire immune system is usually suppressed and the body's ability to respond to infections is also severely compromised. Typical drugs in this class include azathioprine, chlorambucil, cyclophosphamide, cyclosporine, or methotrexate. Corticosteroids that reduce inflammation and suppress the immune response can cause side effects when using long-term treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) can reduce pain and inflammation, yet exhibit considerable side effects. Alternative treatments include agents that activate or block cytokine signaling. Orally active compounds with immunomodulatory properties, no compromised immune responses and reduced side effects would significantly improve current treatments of uncontrolled inflammatory disease.

In the field of organ transplantation the host immune response has to be suppressed to prevent organ rejection. Organ transplant recipients may experience some rejection even when taking immunosuppressive drugs. Rejection occurs most often within the first few weeks after transplantation, but episodes of rejection can also occur months or even years after transplantation. Combinations of up to three or four medications are commonly used to give maximum protection against rejection while minimizing side effects. Current standard drugs used to treat organ rejection interfere with discrete intracellular routes in the activation of T-type or B-type white blood cells. Examples of such drugs are cyclosporine, daclizumab, basiliximab, everolimus, or FK506, which interfere with cytokine signaling or release; azathioprine or leflunomide, which inhibit nucleotide synthesis; or 15-deoxypergualine, a leukocyte differentiation inhibitor.

The beneficial effects of broad immunosuppressive therapies relate to their effects; however, the widespread immunosuppression that these drugs produce diminishes the system's defense against infection and malignancies. In addition, standard immunosuppressive drugs are often used at high dosages and can cause accelerated organ damage.

Description of the invention

The present invention provides novel compounds of Formula (I) which are S1P1 / EDG1 G-copulated protein receptor agonists and have a powerful and long-lasting immunosuppressive effect that is achieved by reducing the number of circulating B-T lymphocytes without affect its maturation, memory, or expansion. The reduction in circulating B / T-lymphocytes as a result of S1P1 / EDG1 agonism, possibly in combination with the observed improvement in endothelial cell layer function associated with S1P1 / EDG1 activation, makes such compounds useful for treating inflammatory disease. uncontrolled and to improve vascular functionality.

The compounds of the present invention may be used alone or in combination with standard T-cell activation inhibitory drugs to provide novel immunosuppressive therapy with a reduced propensity for infections as compared to standard immunosuppressive therapy. In addition, the compounds of the present invention may be used in combination with reduced dosages of traditional immunosuppressive therapies, to provide effective immunosuppressive activity on the one hand while reducing end organ damage associated with higher doses of standard immunosuppressive drugs. Observation of improved endothelial cell layer function associated with S1P1 / EDG1 activation provides additional benefits of compounds for enhancing vascular function.

The nucleotide sequence and amino acid sequence for the human S1P1 / EDG1 receptor are known in the art and are published in for example: Hla, T., and Maciag, T. J. Biol Chem. 265 (1990), 9308-9313; WO 91/15583 published October 17, 1991; WO 99/46277 published September 16, 1999. The potency and efficacy of the compounds of Formula (I) are tested using a GTPyS assay to determine EC50 values and by measuring rat circulating lymphocytes after oral administration, respectively ( see Examples).

The following paragraphs provide definitions of the various chemical groups that make up the compounds according to the invention and are intended to be applied uniformly throughout the specification and claims unless a differently expressed definition described provides a broader definition.

The term C1-5-alkyl, alone or in combination with other groups, means saturated, branched or preferably straight chain groups of one to five carbon atoms, preferably one to three carbon atoms. Examples of C1-5 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and n-pentyl.

The term C 1-5 alkoxy, alone or in combination with other groups, means an R-O group, wherein R is a C 1-5 alkyl. Preferred C1-5 alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy.

The term C 2-5 alkoxy hydroxy means a straight or branched alkoxy chain having a hydroxy group with which there are at least two carbon atoms between the hydroxy group and oxygen of the C 2-5 alkoxy group. Examples C2-5-alkoxy hydroxy groups are 2-hydroxy-ethoxy, 3-hydroxy-propoxy, 2-hydroxy-propoxy, 4-hydroxy-butoxy, 3-hydroxy-1-methyl-propoxy, 3-hydroxy-butoxy , etc.

The term C1-5-alkylamino or di- (C1-5-alkyl) amino, alone or in combination with other groups, means a group R1-NH- or a group R1-NR "-, respectively, in which R 'and R' are each independently a C1-5 alkyl group. Preferred examples of C1-5 alkylamino or di (C1-5 alkyl) amino groups are methylamino, ethylamino, N, N-dimethylamino, and N-methyl-N-ethylamino.

The term halogen means fluorine, chlorine bromine or iodine, preferably fluoro or chlorine.

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, it is intended to also mean a single compound, salt, or the like.

Any reference hereinbefore or hereinafter to a compound of Formula (I) is to be understood as also referring to configurational isomers such as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures. diastereomeric racemates, as well as salts (especially pharmaceutically acceptable salts) and solvent complexes (including hydrates) of such compounds, and morphological forms, as appropriate and expedient.

Salts are preferably pharmaceutically acceptable salts of the compounds of Formula (I).

Salt-forming groups are groups or radicals having basic or acidic properties. Compounds having at least one basic group or at least one basic radical, for example amino, a secondary amino group not forming a peptide bond or a pyridyl radical, may form acid addition salts, for example with inorganic acids. When several basic groups are present mono- or polyacid addition salts may be formed.

Compounds having acidic groups, such as a carboxyl group or a phenolic hydroxy group, may form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or of calcium, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri- (2-hydroxyethyl) -amine, or heterocyclic bases, for example N-ethylpiperidine or N, N 'dimethyl piperazine.

Mixtures of salts are possible.

Compounds having both acidic and basic groups may form internal salts.

For the purposes of isolation or purification, as well as for compounds which are additionally used as intermediates, the use of pharmaceutically unacceptable salts, for example picrates, is also possible. Only non-toxic pharmaceutically acceptable salts may be used for therapeutic purposes, however, and these salts are therefore preferred.

The term pharmaceutically acceptable salts includes salts with either organic acids or inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, phosphorous acid, nitrous acid, citric acid, formic acid, acid acetic, oxalic acid, maleic acid, lactic acid, tartaric acid, fumaric acid, benzoic acid, mandelic acid, cinnamic acid, pamoic acid, stearic acid, glutamic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid, p -toluenesulfonic acid, salicylic acid, succinic acid, trifluoroacetic acid, and the like which are non-toxic to living organisms or where the compound of Formula (I) is acidic in nature with an inorganic base such as an alkali metal base or alkaline earth metal, for example sodium hydroxide, potassium hydroxide, calcium hydroxide and similar. For other examples of pharmaceutically acceptable salts, reference may be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

The compounds of Formula (I) may contain asymmetric carbon atoms. Substituents on a double bond may be present in cis - (= Z) or trans (= E) form unless otherwise indicated. The compounds of Formula (I) may therefore be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known per se, for example by column chromatography, thin layer chromatography, HPLC or crystallization.

(i) The invention relates to the novel thiophene compounds of Formula (I).

Formula (I)

in which

ring A represents

<formula> formula see original document page 8 </formula>

or

R1 represents hydrogen, C1-5-alkyl, C1-5-alkoxy, or halogen;

R2 represents hydrogen, C1-5-alkyl, C1-5-alkoxy, trifluoromethyl, trifluoromethoxy, or halogen;

R3 represents hydrogen, C1-5-hydroxy-alkyl, 2,3-dihydroxypropyl, di- (C1-5-hydroxy-alkyl) -C1-5-alkyl, -CH2- (CH2) k-NR31R32, (azetidine-3-carboxylic acid) -1-yl methyl, (C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl methyl, 2 - [(azetidine-3-carboxylic acid) - 1-yl] ethyl, 2 - [(C1-5-alkyl-azetidine-3-carboxylic acid ester) -1-yl] -ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -propyl, (pyrrolidine-3-carboxylic acid) -1-yl-methyl, (C1-5- pyrrolidine-3-carboxylic acid alkyl ester) -1-yl methyl, (pyrrolidine-2-carboxylic acid) -1-yl methyl, (C10-pyrrolidine-2-carboxylic acid) alkyl ester ylmethyl, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid) -1-yl] ethyl ester, 2 - [(pyrimidin-2-carboxylic acid) -1-yl] ethyl, 2 - [(C10-pyrrolidin-2-carboxylic acid) -1-yl] -e ester 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] propyl, 3 - [(C1-5-alkyl-pyrrolidin-3-carboxylic acid) -1-yl] propyl, 3-yl [(pyrrolidine-2-carboxylic acid) -1-yl] propyl, 3 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid ester) -1-yl] propyl, -CH2- (CH2) n-COOH5 -CH2- (CH2) n- CONR31R32, -CO-NHR31, - (CH2) nCH (OH) -CH2-NR31R32, C1-5-alkoxy hydroxy, fluoro-C10-alkoxy, C2-5-hydroxy alkoxy, di (C1-5-alkyloxy) -C1-5-alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH2- (CH2) m-NR R, 2 - pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C1-5-alkyl) -piperazin-1-yl] -ethoxy , 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl-propoxy, 3- [4- (C1-5-alkyl) -piperazin-1-one yl] propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2- [ (azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -et 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 2 - [(C10-alkyl-pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 2 - [( pyrrolidin-2-carboxylic acid) -1-yl] ethoxy, 2 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid) -1-yl] ethoxy, 2 - [(2-hydroxy) pyrrolidin) -1-yl] ethoxy, 2 - [(3-hydroxy-pyrrolidin) -1-yl] ethoxy, 3 - [(azetidin-3-carboxylic acid) -1-yl] propoxy, 3 - [( C10-Alkylidine-3-carboxylic acid) -1-yl] -propoxy acid, 3 - [(p -Olidine-3-carboxylic acid) -l-yl] -propoxy, 3 - [(C1-5-alkyl- pyrrolidine-3-carboxylic acid) -1-yl] propoxy ester, 3 - [(pyrrolidine-2-carboxylic acid) -1-yl] propoxy ester, 3 - [(C1-5-alkyl ester of pyrrolidine acid -2-carboxylic) -1-yl] propoxy, 3 - [(2-hydroxy-pyrrolidine) -1-yl] propoxy, 3 - [(3-hydroxy-pyrrolidine) -1-yl] propoxy, 2 -amino-3-hydroxy-2-hydroxymethyl propoxy, -O-CH2-CONR R, 3-carbamoylpropoxy, 3- (C1-5-alkylcarbamoyl) propoxy, 3- (2-hydroxyethylcarbamoyl) ) propoxy, -OCH2-CH (OH) -CH2 -Nr3 1r32,3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl ] -2-hydroxypropoxy, 2-hydroxy-3 - [(pyrrolidine-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C1,5-alkyl ester of pyrrolidine 3-carboxylic) -1-yl] propoxy, 2-hydroxy-3 - [(pyrrolidin-2-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C1,5-alkyl ester pyrrolidine-2-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(2-hydroxy-pyrrolidine) -1-yl] propoxy, 2-hydroxy-3 - [(3-hydroxy) pyrrolidine) -1-yl] propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3- [4- (C1- 5-alkyl) piperazin-1-yl] propoxy, 2-hydroxy-3- [4- (2-hydroxyethyl) piperazin-1-yl] propoxy, 2-hydroxy-3-morpholin-4-one yl-propoxy, -NR 31 R 32, -NHCO-R 31, -CH 2 - (CH 2) k -NHSO 2 R 33j - (CH 2) n CH (OH) -CH 2 -NHSO 2 R 33, -OCH 2 - (CH 2) m -NHSO 2 R 33, -0CH 2 -CH (OH ) -CH 2 -NHSO 2 R 33, -CH 2 - (CH 2) k -NHCOR 34, - (CH 2) n CH (OH) -CH 2 -N HCOR34, -OCH2- (CH2) m-NHCOR34, or -OCH2-CH (OH) -CH2-NHCOR34;

R31 represents hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethyl ethyl, 2-C1-5-alkoxyethyl, 3-hydroxypropyl, 3-C1-5-alkoxy-propyl, 2-amino-ethyl, 2- (C1-5-alkylamino) ethyl, 2- (di- (C1-5-alkyl) amino) ethyl, carboxymethyl, C10 -alkylcarboxymethyl, 2-carboxyethyl, or 2- (C1-5-alkylcarboxy) ethyl;

R31 represents hydrogen, methyl, or ethyl;

R33 represents methyl, ethyl, propyl, isopropyl, butyl, 2-hydroxyethyl, 2-methoxyethyl, methyl-amino, ethyl-amino, propyl-amino, isopropyl-amino, n-butyl-amino, or dimethyl-amino ;

R34 represents hydroxymethyl, hydroxyethyl, aminomethyl, methylamino-methyl, dimethylamino-methyl, amino-ethyl, 2-methyl-amino-ethyl, or 2-dimethyl-amino-ethyl;

k represents the integer 1, 2, or 3;

m represents the integer 1 or 2;

η represents 0, 1, or 2; and

R4 represents hydrogen, C1-5 alkyl, or halogen; and configurational isomers such as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts and solvent complexes of such compounds, and morphological forms.

ii) A particular embodiment of the invention relates to thiophene derivatives according to embodiment i), wherein R3 represents hydrogen, hydroxy-C10-alkyl, 2,3-dihydroxy-propyl, di- (hydroxy-C1- 5-alkyl) -C1-5-alkyl, -CH2- (CH2) k-NR31R32, (azetidine-3-carboxylic acid) -1-ylmethyl, (C1-5-alkyl ester of azetidine-3-acid carboxylic acid) -1-ylmethyl, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethyl, 2 - [(C10-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(C1-5-alkyl-ester of azetidine-3-carboxylic acid) -1-yl] -propyl, ( pyrrolidine-3-carboxylic acid) -1-ylmethyl, (C10-alkyl-pyrrolidine-3-carboxylic acid ester) -1-ylmethyl, (pyrrolidine-2-carboxylic acid) -1-ylmethyl, (C 1-6 -Pyrrolidine-2-carboxylic acid ester) -1-yl-methyl, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] -ethyl, 2 - [(C1-5-alkyl- pyrrolidin-3-carboxylic acid) -1-yl] ethyl ester, 2 - [(acid pyrrolidin-2-carboxylic) -1-yl] ethyl, 2 - [(C1-5-alkyl ester of pinolidin-2-carboxylic acid) -1-yl] ethyl, 3 - [(pyrrolidine-3-acid carboxylic) -1-yl] propyl, 3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl] propyl, 3 - [(pyrrolidine-2-carboxylic acid) -1 - yl] -propyl, 3 - [(C 1-6 -pyrolidin-2-carboxylic acid) -1-yl] propyl, -CH2- (CH2) n-CONR31R32, -CO-NHR31, - (CH2) nCH (OH) -CH2- NR31 R32, C1-5-alkoxy hydroxy, fluoro-C1-5-alkoxy, hydroxy-C2-5-alkoxy, di (hydroxy-C1-5-alkyl) -C1-5-alkoxy -1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2- (CH2) m-NR31 R32, 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2 -piperazin-1-yl-ethoxy, 2- [4- (C1-5-alkyl) -piperazin-1-yl] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl-propoxy, 3- [4- (C1-5-alkyl) -piperazin-1-yl] -propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin- 1-yl] propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2 - [(azeti acid dina-3-carboxylic) -1-yl] -ethoxy, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidine-3-acid carboxylic) -1-yl] ethoxy, 2 - [(C1-5 alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl] ethoxy, 2 - [(pyrrolidine-2-carboxylic acid) -1 -yl] -ethoxy, 2 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid ester) -1-yl] -ethoxy, 2 - [(2-hydroxy-pyrrolidine) -1-yl] -ethoxy , 2 - [(3-hydroxypyrrolidine) -1-yl] ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(C10-alkyl ester of azetidine -3-carboxylic) -1-yl] propoxy, 3 - [(pyrrolidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(C1-5 alkyl-pyrrolidine-3-carboxylic acid ester ) -1-yl] propoxy, 3 - [(pyrrolidine-2-carboxylic acid) -1-yl] propoxy, 3 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid ester) -1- yl] -propoxy, 3 - [(2-hydroxy-pyrrolidine) -1-yl] -propoxy, 3 - [(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2 -hydroxymethyl propoxy, -O-CH2-CON R31R32,3-carbamoylpropoxy, 3- (C1-5-alkylcarbamoyl) propoxy, 3- (2-hydroxyethylcarbamoyl) propoxy, -OCH2-CH (OH) -CH2-Nr31r32.3 - [( azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 2-hydroxy-3 - [(pyrrolidine-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C10-alkyl-pyrrolidine-3-carboxylic acid) -1-yl] - propoxy, 2-hydroxy-3 - [(pyrrolidine-2-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C1-5-alkyl ester of pyrrolidine-2-carboxylic acid) -1 -yl] propoxy, 2-hydroxy-3 - [(2-hydroxy-pyrrolidine) -1-yl] -propoxy, 2-hydroxy-3 - [(3-hydroxy-pyrrolidine) -1-yl] -propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3- [4- (C1-5-alkyl) -piperazin-1-yl ] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, -NR31R32, -NHCO- R31, -CH2- (CH2) k-NHSO2 R33, - (CH2) nCH ( OH) -CH 2 -NHSO 2 R 33, -OCH 2 - (CH 2) m -NHSO 2 R 33, -OCH 2 -CH (OH) -CH 2 -NHSO 2 R 33, -CH 2 - (CH 2) k -NHCOR 34, - (CH 2) n CH (OH) -CH 2 - NHCOR34, -OCH2- (CH2) m -NHCOR34, or -OCH2 -CH (OH) -CH2-NHCOR34 and wherein R31, R32, R33 and R34 are as defined above in embodiment i).

iii) A particular embodiment of the invention relates to thiophene derivatives according to embodiment i) or ii), wherein the compounds represented in Formula (I) constitute the (laR, 5aS) isomer of the 1,1-derivative. , 2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene.

iv) A preferred embodiment of the invention relates to thiophene derivatives according to embodiment i) or ii), wherein the compounds represented in Formula (I) constitute the (1S, 5aR) isomer of the 1.1 derivative. 2,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene.

v) A preferred embodiment of the invention relates to thiophene derivatives according to embodiment i) to iv), wherein the compounds represented in Formula (I) constitute a 5-thiophen-2-yl- [1, 2,4] oxadiazole.

vi) Another preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) to iv), wherein the compounds represented in Formula (I) constitute a 3-thiophen-2-yl- [ 1,2,4] oxadiazole.

vii) A preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) to vi), wherein R 1, R 2, and R 4 represent hydrogen.

viii) Another preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) to vi), wherein R1 represents hydrogen and R2 and R4 represent a methyl group.

ix) Another preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) to vi), wherein R 1 represents hydrogen, R 2 represents a methyl group and R 4 represents an ethyl group.

x) Another preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) to vi), wherein R 1 represents hydrogen, R 2 represents a methoxy group and R 4 represents chloro.

xi) Another preferred embodiment of the invention relates to thiophene derivatives according to any of embodiments i) ax), wherein R represents hydrogen, C1-5-hydroxy-alkyl, 2,3-dihydroxy-propyl di- (hydroxy-C1-5-alkyl) -C1-5-alkyl, -CH2- (CH2) k-NR31R32, (azetidine-3-carboxylic acid) -1-yl-methyl, (C1-5-alkyl azetidine-3-carboxylic acid ester) -1-yl methyl, 2 - [(azetidin-3-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl ester of azetidine acid -3-carboxylic) -1-yl] ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] propyl, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid ) -1-yl] -propyl, (pyrrolidine-3-carboxylic acid) -1-yl-methyl, (C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl-methyl, (pyrrolidine acid -2-carboxylic) -1-ylmethyl, (C1-5-alkylpyrrolidine-2-carboxylic acid ester) -1-ylmethyl, 2 - [(pyrrolidine-3-carboxylic acid) -1-yl ] -ethyl, 2 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester co) -1-yl] ethyl, 2 - [(pyrrolidine-2-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid ester) -1 -yl] ethyl, 3 - [(pyrrolidine-3-carboxylic acid) -1-yl] propyl, 3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid) -1-yl] - propyl, 3 - [(pyrrolidin-2-carboxylic acid) -1-yl] -propyl, 3 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid) -1-yl] -propyl, -CH2 - (CH2) n-COOH, -CH2- (CH2) n-CONR31R32, -CO-NHR31, - (CH2) nCH (OH) -CH2-NR31R32, hydroxy C1-6 alkoxy, Auoro-C1-5-alkoxy, hydroxy -C2.5-alkoxy, di (C1-5-hydroxy-C1-alkyl) alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH2- (CH2) m -NR R, 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C10-alkyl) -piperazin-1-yl ] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl-propoxy, 3- [4- (C1-5-alkyl) -piperazin -1-yl] propoxy, 3- [4- (2-hydroxyethyl) piperazin-1-yl] propoxy, 2-morpholin-4-yl-ethoxy 1,3-morpholin-4-yl-propoxy, 2 - [(azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) - 1-yl] -ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(C1-5-C1-6 alkyl ester? pyrolidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidine-2-carboxylic acid) -1-yl] ethoxy, 2 - [(C1-5 alkyl ester of pyrrolidine-2 - carboxylic) -1-yl] ethoxy, 2 - [(2-hydroxypyrrolidine) -1-yl] ethoxy, 2 - [(3-hydroxypyrrolidine) -1-yl] ethoxy, 3 [ (azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(pyrrolidine acid 3-carboxylic) -1-yl] propoxy, 3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl] propoxy, 3 - [(pyrrolidine-2-carboxylic acid) - 1-yl] propoxy, 3 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid ester) -1-yl] -propoxy, 3 - [(2-hydroxy-pyrrolidine) -1-yl] -propoxy, 3 - [(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxymethyl-propoxy, -O-CH 2 -CONR R,

3-carbamoyl propoxy, 3- (C1-5-alkylcarbamoyl) propoxy, 3- (2-hydroxy-ethylcarbamoyl) propoxy, -OCH2-CH (OH) -CH2-Nr3 1r32, 3 - [(acid azetidine-3-carboxylic) -1-yl] -2-hydroxy-propoxy, 3 - [(C1-5-alkyl ester of azetidin-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, 2 -hydroxy-3 - [(pyrrolidin-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C1-5-alkyl pyrrolidin-3-carboxylic acid) -1-yl] ester -propoxy, 2-hydroxy-3 - [(pyrrolidine-2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3 - [(C1-5-alkyl ester of pyrrolidine-2-carboxylic acid) - 1-yl] propoxy, 2-hydroxy-3 - [(2-hydroxy-pyrrolidine) -1-yl] -propoxy, 2-hydroxy-3 - [(3-hydroxy-pyrrolidine) -1-yl] -propoxy 2,2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3- [4- (C 1-5-alkyl) -piperazin-1-yl] - propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, or -NR31R32, -NHCO- R31 and in which R31 and R32 are co as defined above in embodiment i).

xii) Another preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) and iii) to

x), wherein R represents hydrogen, C1-5-hydroxy-alkyl, 2,3-dihydroxy-propyl, di (C10-hydroxy-C1-5-alkyl-alkyl, -CH2- (CH2) k-NR31R32 , (azetidine-3-carboxylic acid) -1-ylmethyl, (C1-5-alkyl azididine-3-carboxylic acid ester) -1-ylmethyl, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl ] -propyl, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -propyl, (pyrrolidine-3-carboxylic acid) -1-yl-methyl, (C1-5 - pyrrolidine-3-carboxylic acid alkyl ester) -1-ylmethyl, (pyrrolidine-2-carboxylic acid) -1-ylmethyl, (C1-5-pyrrolidine-2-carboxylic acid alkyl ester) -1-yl-methyl, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] -ethyl, 2 - [(C1-5-alkyl-pyrrolidin-3-carboxylic acid) -1-yl] -benzamide ethyl, 2 - [(pyrrolidine-2-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid) ester 1-yl] ethyl, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] propyl, 3 - [(C1-5-alkyl-pyrrolidin-3-carboxylic acid ester) -1-yl] -propyl, 3 - [(pyrrolidine-2-carboxylic acid) -1-yl] -propyl, 3 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid) -1-yl] -propyl ester, - CH2- (CH2) n -COOH5 -CH2- (CH2) n- CONR31R32j -CO-NHR31, - (CH2) nCH (OH) -CH2-NR31R32, C1-5 alkoxy hydroxy, C1-5 fluoro alkoxy, C2.5-alkoxy hydroxy, di (C1-5-hydroxy-C1-alkyl) alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH2- (CH2) m-NR31R32, 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C1-5-alkyl) -piperazin-1 -yl] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl-propoxy, 3- [4- (C1-5-alkyl) -piperazin-1-yl] propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl- propoxy, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid o) -1-yl] ethoxy, 2 - [(pyrrolidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1 2-yl] -ethoxy, 2 - [(pyrimidin-2-carboxylic acid) -1-yl] -ethoxy, 2 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid) -1-yl] -benzamide ethoxy, 2 - [(2-hydroxy-pyrrolidine) -1-yl] -ethoxy, 2 - [(3-hydroxy-pyrrolidine) -1-yl] -ethoxy, 3 - [(azetidine-3-carboxylic acid) - 1-yl] propoxy, 3 - [(C) .5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, 3 - [(C1-5-alkyl-pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidin-2-carboxylic acid) -1-yl] -propoxy, 3 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid) -1-yl] -propoxy, 3 - [(2-hydroxy-pyrrolidine) -1-yl] -propoxy, 3 - [(3 - hydroxypyrrolidine) -1-yl] propoxy, 2-amino-3-hydroxy-2-hydroxymethyl propoxy, -O-CH2-CONR31R32, 3-carbamoylpropoxy, 3- (C1.5-alkylcarbamoyl) ) propoxy, 3- (2-hydroxyethylcarb) moyl) propoxy, -OCH2 -CH (OH) -CH2-Nr31r32,3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3 - [(C1-5-alkyl-ester azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 2-hydroxy-3 - [(pyrrolidine-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [ Pyrrolidin-3-carboxylic acid (C 1-5 alkyl ester) -1-yl] propoxy, 2-hydroxy-3 - [(pyrrolidin-2-carboxylic acid) -1-yl] propoxy, 2-hydroxy -3 - [(C1,5-alkyl-pyrrolidine-2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3 - [(2-hydroxy-pin-olidine) -1-yl] -propoxy 2-hydroxy-3 - [(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy 2-hydroxy-3- [4- (C1-5-alkyl) piperazin-1-yl] propoxy, 2-hydroxy-3- [4- (2-hydroxyethyl) piperazin-1-yl] -propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, or -NR 31 R 32, -NHCO-R 31 and wherein R 31 and R 32 are as defined above in embodiment i).

xiii) Another preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) ax), wherein R3 represents hydroxy-C2-5-alkoxy, di (hydroxy-C1-5-alkyl) C1-5-alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH2- (CH2) m-NR R32, 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-2-one 1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C1-5-alkyl) -piperazin-1-yl] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] ethoxy, 3-piperazin-1-yl-propoxy, 3- [4- (C1-5-alkyl) -piperazin-1-yl] -propoxy, 3- [4- (2- hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2 - [(azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidine-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(C10-alkyl-pyrrolidin-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidin-2-carboxylic acid) -l-yl] -ethoxy, 2 - [(C1-5 pyrrolidine-2-carb acid alkyl ester oxyl) -1-yl] ethoxy, 2 - [(2-hydroxy-pyrrolidine) -1-yl] ethoxy, 2 - [(3-hydroxy-pyrrolidine) -1-yl] ethoxy, 3 - [( azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(pyrrolidine-3 acid -carboxylic) -1-yl] propoxy, 3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl] -propoxy, 3 - [(pyrrolidine-2-carboxylic acid) - 1-yl] propoxy, 3 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid ester) -1-yl] -propoxy, 3 - [(2-hydroxy-pyrrolidin) -1-yl] -benzamide propoxy, 3 - [(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxy-methylpropoxy, -O-CH2-CONR31R32, 3-carbamoyl-propoxy, 3 - (C10-alkylcarbamoyl) propoxy, 3- (2-hydroxy-ethylcarbamoyl) propoxy, -OCH 2 -CH (OH) -CH 2 -N, 31,32,3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 2-hydroxy-3- [ (pyrrolidine-3-carboxylic acid) -1-yl] -pro Poxy, 2-hydroxy-3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3 - [(pyrrolidine-2-carboxylic acid) -1 -yl] -propoxy, 2-hydroxy-3 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid ester) -1-yl] -propoxy, 2-hydroxy-3 - [(2-hydroxy-pyrirolidine ) -1-yl] -propoxy, 2-hydroxy-3 - [(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3 -piperazin-1-yl-propoxy, 2-hydroxy-3- [4- (C1-5-alkyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl ) -piperazin-1-yl] -propoxy, or 2-hydroxy-3-morpholin-4-yl-propoxy and wherein R31 and R32 are as defined above in embodiment i).

xiv) Another preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) ax), wherein R represents C1-5 hydroxy-alkyl, 2,3-dihydroxypropyl, - (hydroxy-C 1-5 alkyl) -C 1-5 alkyl, -CH 2 - (CH 2) k -NR, R (azetidine-3-carboxylic acid) -1-yl methyl, (C 1-5 alkyl) azetidine-3-carboxylic acid ester) -1-ylmethyl, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl ester of azetidine acid 3-carboxylic) -1-yl] ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] propyl, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -propyl, (pyrrolidine-3-carboxylic acid) -1-yl-methyl, (C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl-methyl, (pyrrolidine-acid) 2-carboxylic) -1-ylmethyl, (C10-alkyl-pyrrolidine-2-carboxylic acid ester) -1-ylmethyl, 2 - [(pyrrolidine-3-carboxylic acid) -1-yl] ethyl , 2 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid) -1-yl] -ethyl ester a, 2 - [(pyrrolidin-2-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid) -1-yl] ethyl ester, 3- 5 [(pyrrolidine-3-carboxylic acid) -1-yl] propyl5 3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl] propyl, 3 - [(pyrrolidine acid -2-carboxylic) -1-yl] propyl, 3 - [(C 1 -C 6 -pyrrolidine-2-carboxylic acid ester) -1-yl] propyl, -CH 2 - (CH 2) n -COOH 5 -CH 2 - (CH2) n -CONR31R325 -CO-NHR315 or - (CH2) nCH (OH) -CH2-NR31R32 and wherein R31 and R32 are as defined above in embodiment i).

xv) Another preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) and iii) ax), wherein R3 represents C1-5 hydroxy-alkyl, 2,3-dihydroxydehyde. propyl, di- (hydroxy-C1-5-alkyl) -C1-5-alkyl, -CH2- (CH2) k-NR31R325 (azetidine-3-carboxylic acid) -1-yl-methyl, (C1-5-alkyl azetidine-3-carboxylic ester) -1-ylmethyl, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl ester of azetidine 3-carboxylic) -1-yl] ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] propyl, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -propyl, (pyrrolidin-3-carboxylic acid) -1-yl-methyl, (C1-5-alkyl-pyrrolidin-3-carboxylic acid ester) -1-yl-methyl5 (pyrrolidine-2 (C1-5-alkyl-pyrrolidine-2-carboxylic acid) -1-yl-methyl-5-2- [(pyrrolidin-3-carboxylic acid) -1-yl] -ethyl5-carboxylic acid 2 - [(C1-5 alkyl-pyrrolidin-3-carboxylic acid) -1-yl] ethyl ester, 2 - [(pyrrolidin-2-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-pyrrolidin-2-carboxylic acid) -1-yl] ethyl ester, 3 - [( pyrrolidine-3-carboxylic acid) -1-yl] propyl5 3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl] propyl5 3 - [(pyrrolidine-2-carboxylic acid ) -1-yl] -propyl, 3 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid ester) -1-yl] -propyl, -CH2- (CH2) n-COOH5 -CH2- (CH2 ) n-CONR31R325 -CO-NHR315 or - (CH2) nCH (OH) -CH2-NR31R32 and wherein R31 and R32 are as defined above in claim 1.

xvi) Another preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) ax), wherein R3 represents di (hydroxy-C1-5-alkyl) -C1-5-alkoxy. -glyceryl, -OCH 2 - (CH 2) m -NR 31 R 32, -O-CH 2 -CONR 31 R 32, or -OCH 2 -CH (OH) -CH 2 -Nr 3 1 R 32, wherein R 31 represents methyl or 2-hydroxyethyl and R represents hydrogen.

xvii) Another very preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) ax), wherein R represents CH 2 - (CH 2) k -NHSO 2 R, - (CH 2) n CH (OH) - CH 2 -NHSO 2 R 33, -OCH 2 - (CH 2) m -NHSO 2 R 33, -OCH 2 CH (OH) -CH 2 -NHSO 2 R 33, -CH 2 - (CH 2) k -NHCOR 34, (CH 2) n CH (OH) -CH 2 -NHCOR 34, -OCH 2 - (CH2) m -NHCOR34, or -OCH2 -CH (OH) -CH2 -NHCOR34 and wherein R33 and R34 are as defined above in embodiment i).

xviii) Another very preferred embodiment of the invention relates to thiophene derivatives according to any one of embodiments i) to x), wherein R 3 represents -CH 2 - (CH 2) n -COOH, -CH 2 - (CH 2) n -. CONR31R32, -CH2- (CH2) k-NHSO2R33, - (CH2) nCH (OH) -CH2-NHSO2R33, -OCH2- (CH2) m-NHSO2R33, -0CH2-CH (OH) -CH2-NHS02R33, -CH2- (CH2) k -NHCOR34, - (CH2) nCH (OH) -CH2-NHCOR34, -OCH2- (CH2) m-NHCOR34, or -OCH2 -CH (OH) -CH2-NHCOR34 and wherein R31, R32, R33 and R34 are as defined above in embodiment i).

(xix) Specific thiophene derivatives according to Formula (I) are:

4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenol,

2- {4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thiacyclopropa [a] pentalen-4 -yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -ethanol,

1- {4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thiacyclopropa [a] pentalen-4- yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol, (2S) -3- {4- [5 - ((laS, 5aR) -1,2,2 -trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propane -1,2-diol,

(2R) -3- {4- [5 - ((laS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen -4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol,

1-methoxy-3- {4- [5 - ((laS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen -4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol,

2- {4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thiacyclopropa [a] pentalen-4 -yl) - [1,2,4] oxadiazol-3-yl] -phenoxy-methyl} -propane-1,3-diol,

3- {4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thiacyclopropa [a] pentalen-4- yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-1-ol,

dimethyl- (2- {4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -amine,

dimethyl- (2- {4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -amine,

2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen -4-yl) - [1,2,4] oxadiazol-3-yl] -phenol,

2- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -ethanol,

1- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol,

(2S) -3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo -propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol,

(2R) -3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3 -thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol,

1- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo -propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -3-methoxy-propan-2-ol,

2- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo -propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy-methyl} -propane-1,3-diol,

3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [ a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-1-ol,

(2- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclohexane) propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -dimethyl-amine,

3- [3,5-dimethyl-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1 a, 5 , 5α-tetrahydro-3-thia-cyclopropa [α] pentalen-4-yl) - [1,2,4] oxadiazole,

4- (2- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3- thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} ethyl) -morpholine,

-3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia- cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propylamine,

(3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [ a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -methylamine,

(3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclohexyl] propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -dimethyl-amine,

2- (3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclohexane propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl-amino) -ethanol,

3- [3,5-dimethyl-4- (3-pyrrolidin-1-yl-propoxy) -phenyl] -5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1 a, 5 , 5α-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazole,

(3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,2,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -propyl-amine,

2- (3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclohexane) propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl-amino) -propane-1,3-diol,

Nr (3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -ethane-1,2-diamine,

1 - (3- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl 1,1a, 5,5a-tetrahydro-3-thia-cyclic acid -prop ([a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -pyrrolidine-2-carboxylic acid,

1- (3- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl 1,1a, 5,5a-tetrahydro-3-thia-cyclic acid -prop ([a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -pyrrolidine-3-carboxylic acid,

2- [4- (3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro- 3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -piperazin-1-yl] -ethanol,

2-amino-2- {2,6-dimethyl-4- [5 - ((1 aS, 5 aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia -cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] phenoxy-methyl} -propane-1,3-diol, (3- {2,6-dimethyl -4- [5 - ((1aS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl ) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -isopropyl-amine,

(3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [ a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) - (2-ethoxy-ethyl) -amine,

2,6-dimethyl-4- [3 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [ a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenol,

2- [2,6-dimethyl-4- [3 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenoxy} -ethanol,

1- [2,6-dimethyl-4- [3 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [ a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenoxy} -propan-2-ol,

3- [2,6-dimethyl-4- [3 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenoxy} -propane-1,2-diol,

3 - [2,6-dimethyl-4- [3 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclohexane propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenoxy} -propane-1,2-diol,

2- [2,6-dimethyl-4- [3 - ((laS, 5aR) -1,1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [ a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenoxy-methyl} -propane-1,3-diol, and

3- (3-trifluoromethyl-phenyl) -5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] pentalen-4-yl) - [1,2,4] oxadiazole.

The compounds of Formula (I) and their pharmaceutically acceptable salts may be used as medicaments, for example in the form of pharmaceutical compositions for enteral, parenteral or topical administration. They may be administered, for example, perorally, for example in the form of tablets, coated tablets, dragees, soft and hard gelatin capsules, solutions, emulsions or suspensions, rectally, for example in the form of suppositories, parenterally, e.g. injection solutions or infusion solutions, or topically, for example in the form of ointments, creams or oils.

Production of pharmaceutical compositions may be effected in a manner which will be familiar to anyone skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the compounds of Formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, in a galenic administration form together with liquid carrier materials. or suitable inert, non-toxic pharmaceutically acceptable solids and, if desired, normal pharmaceutical adjuvants.

Pharmaceutical compositions comprising a compound of Formula (I) are useful for the prevention and / or treatment of diseases or disorders associated with an activated immune system.

Such diseases or disorders are selected from the group consisting of rejection of selected transplanted organs of kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host diseases caused by stem cell transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, psoriatic arthritis, and thyroiditis such as Hashimoto's thyroiditis, uveoretinitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; asthma; type I diabetes; postinfectious autoimmune diseases including rheumatic fever and postinfectious glomerulonephritis; solid cancers and tumor metastasis. Preferably, the diseases or disorders to be prevented or treated with the compounds of Formula (I) are selected from the group consisting of rejection of selected transplanted organs from the group consisting of rejection of selected transplanted organs from kidney, liver. , heart and lung; graft-versus-host diseases caused by stem cell transplantation; selected autoimmune syndromes of rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease, and Hashimoto's thyroiditis; and atopic dermatitis.

The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a patient a pharmaceutically effective amount of a compound of Formula (I).

In addition, the compounds of Formula (I) are also useful, in combination with one or more immunomodulatory agents, for the prevention and / or treatment of the diseases and disorders mentioned herein. According to a preferred embodiment of the invention, said agents are selected from the group consisting of immunosuppressants, corticosteroids, NSAID's, cytotoxic drugs, adhesion molecule inhibitors, cytokines, cytokine inhibitors, cytokine receptor antagonists and recombinant cytokine receptors.

Yet another object of the present invention is a process for preparing a pharmaceutical composition comprising a compound of Formula (I) by mixing one or more active ingredients with inert excipients in a per se known manner.

The present invention also relates to the use of a compound of Formula (I) for the preparation of a pharmaceutical composition, optionally for use in combination with one or more immunomodulatory agents, for the prevention and / or treatment of the diseases and disorders herein. mentioned. The present invention also relates to prodrugs of a compound of Formula (I) which convert in vivo to the compound of Formula (I) as such. Any reference to a compound of Formula (I) is therefore to be construed as also referring to the corresponding prodrugs of the compound of Formula (I), as appropriate and expedient.

The compounds of Formula (I) may be manufactured by the methods given below, by the methods given in the Examples or by analogous methods. Optimal reaction conditions may vary with the particular solvents or reagents used, but such conditions may be determined by one of ordinary skill in the art by routine optimization procedures.

The compounds of Formula (I) of the present invention may be prepared according to the general reaction sequence described below. Just a few possibilities of synthesis giving the compounds of

Formula (I) are described.

Compounds of Formula (I), wherein Formula (I) represents a 5-thiophen-2-yl [1,2,4] oxadiazole derivative, are prepared by reacting a compound of Structure 1 in a solvent such as xylene, toluene, benzene, pyridine, DMF, dichloromethane, acetic acid, trifluoroacetic acid, etc. at rt or at elevated temperatures in the presence or absence of auxiliaries such as acids (eg TFA, acetic acid, HCl, etc.), bases (eg NaH, NaOAc, Na2CO3, K2CO3, triethylamine, etc.), tetraalkyl salts -ammonium, or water scavengers (e.g. oxalyl chloride, a carboxylic acid anhydride, POCl3, PCl5, P4O10, molecular sieves, etc.) (Lit: eg AR Gangloff, J. Litvak, EJ Shelton, D. Sperandio, VR Wang, KD Rice 3 Tetrahedron Lett. 42 (2001), 1441-1443; T. Suzuki, K. Iwaoka, N. Imanishi, Y. Nagakura, K. Miyta, H. Nakahara, M. Ohta, T. Mase, Chem Pharm Buli 47 (1999), 120-122, RF Poulain, AL Tartar, P. P. Deprez, Tetrahedron Lett. 42 (2001), 1495-1498, RM Srivastava, FJS Oliveira, DS Machado, RM Souto - Major, Synthetic Commun., 29 (1999), 1437-1450; O. John, JM Shreeve, Inorganie Chemistry 27 (1988), 3100-3104, B. Kaboudin, K. Navaee, Heterocyeles 60 (2003), 2287 -2292).

<formula> formula see original document page 28 </formula>

Structure 1

Structure 1 compounds can be prepared by reacting a structure 2 compound with a structure 3 compound in a solvent such as DMF, THF, etc. in the presence or absence of one or more copulating agents such as TBTU, DCC, EDC, HBTU, HOBt, CDI, etc. and in the presence or absence of a base such as triethylamine, Hünig base, NaH, K2CO3, etc. (Lit. for example A. Hamze, J.-F. Hernandez, P.Fulcrand, J. Martinez. J. Org. Chem. 68 (2003) 7316-7321; and the literature cited above).

<formula> formula see original document page 28 </formula>

Compounds of Structure 3 may be prepared by reacting a compound of Structure 4 with hydroxylamine or one of its salts in a solvent such as methanol, ethanol, pyridine, etc. in the presence or absence of a base such as Na 2 CO 3, K 2 CO 3, triethylamine, etc. (Lit. for example T. Suzuki, K. Iwaoka, N. Imanishi, Y. Nagakura, K. Miyta, H. Nakahara, M. Ohta, T. Mase, Chem. Pharm. Bull. 47 (1999), 120- 122; J. Cui, D. Crich, D. Wink, M. Lam, AL Rheingold, DA Case, WT Fu, Y. Zhou, M. Rao, AJ Olson, E. Johnson, Bioorg. 11 (2003), 3379-3392; R. Miller F. Lang, ZJ Song, D. Zewge, WO 2004/035538; B. Kaboudin, K. Navaee, Heterocycles 60 (2003), 2287-2292).

<formula> formula see original document page 29 </formula>

Structure 4

Depending on the nature of the features present in residues R1 to R4 in Structures 1, 3 or 4, and in Formula (I), these features may require temporary protection. Suitable protecting groups are known to a person skilled in the art and include for example a benzyl group or a trialkyl silyl group to protect an alcohol, a ketal to protect a diol, etc. These protecting groups may be employed according to standard methodology (e.g. T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley New York, 1991; P.J. Kocienski, Protecting Groups, Thieme Stuttgart9 1994). Alternatively, the desired residues R1 to R4, in particular R3, may also be introduced at subsequent steps following cyclization of a Structure 1 compound by carrying out the above reaction sequence with suitable precursors of the Structure 1, 3 and 4 compounds. respectively. The compounds of Structure 4 or precursors thereof are either commercially available or prepared according to procedures known to one skilled in the art. The compound of Structure 2 may be prepared by reacting a compound of Structure 5 with an aqueous base such as aq. NaOH, aq. LiOH, aq. or an acid such as aq. HCl, TFA, etc. in a solvent such as water, ethanol, methanol, THF, etc. or mixtures thereof.

<formula> formula see original document page 30 </formula>

Structure 5

The Structure 5 compounds are prepared by treating a Structure 6 compound with a non-aqueous base such as NaOMe, NaOEt, KO-tert-Bu, DBU, etc. in a solvent such as methanol, ethanol, THF, DMF, etc. or mixtures thereof preferably at elevated temperatures.

<formula> formula see original document page 30 </formula>

The compounds of Structure 6 are prepared by treating a compound of Structure 7 with a 2-mercapto acetic acid ester in the presence of a base such as NaH in THF, dioxane, DMF, or mixtures thereof. In addition, the compound of Structure 2 may also be prepared in a three-step pot procedure starting from the compound of Structure 7 following the above reaction sequence. <formula> formula see original document page 31 </formula>

Compounds of Formula (I), wherein Formula (I) represents a 3-thiophen-2-yl [1,2,4] oxadiazole derivative, are prepared by reacting a compound of Structure 8 in a solvent such as xylene , toluene, benzene, pyridine, DMF, dichloromethane, acetic acid, trifluoroacetic acid, etc. at rt or at elevated temperatures in the presence or absence of auxiliaries such as acids (eg TFA, acetic acid, HCl, etc.), bases (eg NaH, NaOAc, Na2CO3, K2CO3, triethylamine, etc.), tetraalkyl salts - ammonium, or water scavengers (e.g. oxalyl chloride, a carboxylic acid anhydride, POCl3, PCI5, P4O10, molecular sieves, etc.) (Lit. for example see above).

<formula> formula see original document page 31 </formula>

Structure Compounds 8 may be prepared by reacting a Structure 9 compound with a Structure 10 compound in a solvent such as DMF, THF, etc. in the presence or absence of one or more copulating agents such as TBTU, DCC, EDC, HBTU, HOBt, CDI, etc. and 31

in the presence or absence of a base such as triethylamine, Hünig base, NaH5 K2CO3, etc. (Lit: for example see above).

<formula> formula see original document page 32 </formula>

The compounds of Structure 9 may be prepared by reacting a compound of Structure 11 with hydroxyl amine or one of its salts in a solvent such as methanol, ethanol, pyridine, etc. in the presence or absence of a base such as Na2COs, K2CO3, triethylamine, etc. (Lit. for example CD Bedford, RA Howd, OD Dailey, A. Miller, HW Nolen, RA Kenley, JR Kern, JS Winterle, J. Med Chem. 29 (1986), 2174-2183, P. Dubus, B. Decroix, J. Morei, P. Pastour, Annales de Chimie (Paris, France) 10 (1975) 331-336, and references above).

Structure 11

Depending on the nature of the features present in residues R1 to R4 in Structures 8, 10 to Formula (I), these features may require temporary protection. Suitable protecting groups are known to one skilled in the art and include for example a benzyl or trialkylsilyl group to protect an alcohol, a ketal to protect a diol, etc. These protecting groups may be employed according to standard methodology (e.g. T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley New York, 1991; P.J. Kocienski, Protecting Groups, Thieme Stuttgart, 1994).

Alternatively, the desired residues R1 to R4, in particular R3, may also be introduced at subsequent steps following cyclization of a Structure 8 compound by performing the above reaction sequence with suitable precursors of Structure 8 and 10 compounds, respectively. The compounds of Structure 10 or precursors thereof are either commercially available or prepared according to procedures known to one skilled in the art.

The Compound 11 may be prepared by reacting the Compound 7 with a Compound 12 in a solvent such as ethanol, methanol, THF, dioxane, DMF or mixtures thereof in the presence of a base such as aq. aq., etc. at temperatures between 20 ° C and 100 ° C (in analogy to B. Hedegaard, J. Z. Mortensen, S. O. Lawesson, Tetrahedron 27 (1971), 38533859; and the preparation of a compound of Structure 5 above).

<formula> formula see original document page 33 </formula>

2- [1-Chloro-ethylidene] -6,6-dimethyl-bicyclo [3.1.0] hexan-3-one (15.5R) -isomer (1-15R) -isomer of Structure 7 ) can be prepared from commercially available (+) - 3-carene according to the procedures given in the literature (eg SA Popov, A. Yu. Denisov, Yu. V. Gatilov, I. Yu. Bagryanskaya and V. V Tkachev, Tetrahedron Asymmetry 5 (1994), 479-489; S. Α. Ρορον, Α V. Tkachev; Synthetic Commun. 31 (2001), 233-243).

The racemic form of Structure 7 can be prepared starting from (+) - 3-carene following the procedures given in the literature (W. Cocker, DH Grayson, Tetrahedron Lett. 51 (1969), 4451-4452; S. Lochynski; B. Jarosz, M. Walkowicz, K. Piatkowski, J. Prakt. Chem. (Leipzig) 330 (1988), 284-288; M. Walkowicz, H. Kuczynsky, C. Walkowicz, Roczniki Chemii Ann. Soc. Chim. Polonorum 41 (1967), 927-937; H. Kuczynski, M. Walkowicz, C. Walkowicz, K. Nowak, IZ Siemion, Roczniki Chemii Ann. Soc. Chim. Polonorum, 38 (1964), 1625-1633; AV Pol, VG Naik, HR Sonawane, Ind. J. Chem., Sect B, 19 (1980) 603-604; SA Popov, A. Yu. Denisov, Yu. V. Gatilov, I. Yu. Bagryanskaya and V. V. Tkachev, Tetrahedron Asymmetry 5 (1994), 479-489, SA Popov, V. V. Tkachev; Synthetic Commun. 31 (2001), 233-243) and is exemplified below.

The compounds of Formula (I) which are based on 2- [1-chloroethylidene] -6,6-dimethyl-bicyclo [3.1.0] hexan-3-one (1 R, 5S) isomer ((1 R, 5S) -isomer of compound of Structure 7) can be obtained by resolving the racemic mixture of the racemic mixture of a compound of Formula (I), or one of its precursors, into their pure enantiomers by a method per se known to a person. skilled in the art, preferably by chromatography or crystallization.

Examples

The following examples illustrate the invention but do not limit its scope.

All temperatures are stated in degrees Celsius.

Compounds are characterized by 1 H-NMR (300 MHz) or 13 C-NMR (75 MHz) (Varian Oxford; chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet; ρ = pentuplet, hex = hexet, hept = heptet, m = multiplet, br = broad, coupling constants are given in Hz); by LC-MS (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: 4.6 mm χ 50 mm, Zorbax SB-AQ, 5 μιη, 12.0 nm gradient: 5-95% acetonitrile in water, 1 min, with 0.04% trifluoroacetic acid, flow: 4.5 mL / min), t R is given in min; by TLC (Merck TLC plates, Silica gel 60 F254); or by melting point. Compounds are purified by preparative HPLC (column: X-ground RP18, 50 mm x 19 mm, 5 μπι, gradient: 10-95% acetonitrile in water containing 0.5% formic acid) or by MPLC (Labomatic MD-80 pump -100, UVIS-201 Linear detector, column: 350 mm x 18 mm, Labogel-RP-18-5s-100, gradient: 10% methanol in water to 100% methanol).

Abbreviations (as used herein)

approx. about

aq. watery

atm atmosphere

BSA bovine serum albumin

Butyl

CC column chromatography

CDI carbonyl diimidazole

DBU 1,8-diazabicyl [5.4.0] undec-7-en

DCC dicyclohexyl carbodiimide

DCM dichloromethane

DEAD diethyl azicarboxylate

DIPEA diisopropyl ethyl amine, Hünig base, ethyl diisopropyl amine

Dimethyl formamide DMF

DMSO dimethyl sulfoxide

DPPP 1,3-bis (diphenylphosphino) propane

EA ethyl acetate

N- (3-dimethyl-amino-propyl) -N'-ethyl-carbodiimide EDC

Et ethyl

hr hour

HBTU 0- (benzotriazol-1-yl) -N, N, N, N'-tetramethyluronium hexafluorophosphate

HOBt 1-hydroxy-benzotriazole

HPLC high performance liquid chromatography

LC-MS liquid chromatography-mass spectrometry

Me methyl

min minute (s)

MPLC medium pressure liquid chromatography

OAc acetate <table> table see original document page 36 </column> </row> <table>

(1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalene-4-carboxylic acid ethyl ester (Compound of Structure 5)

<formula> formula see original document page 36 </formula>

a) NaH (7.0 g, 60% dispersion in mineral oil, 175 mmol) is washed with pentane (100 mL) before being suspended in THF (400 mL). The suspension is cooled to 0 ° C and a solution of ethyl 2-mercaptoacetate (12.62 g, 105 mmol) in THF (50 mL) is added over a period of 20 min. The reaction temperature is maintained at 5-10 ° C. Upon completion of the addition, cooling is removed and stirring is continued for 30 min. A solution of (1S, 5R) -2- (1-chloro- (E) -ethylidene) -6,6-dimethyl-bicyclo [3,1,0] hexan-3-one (SA Popov, A. Yu. Denisov, Yu. V. Gatilov, I. Yu. Bagryanskaya and V. V. Tkachev, Tetrahedron Asymmetry 5 (1994), 479-489; SA Popov, AV Tkachev; Synthetic Commun. 31 (2001), 233-243) ( 12.93 g, 70 mmol) in THF (50 mL) is added to the suspension and the resulting mixture is stirred for 1.5 h at rt. The mixture is filtered, the filtrate is concentrated to about 100 mL, diluted with aq. 1 M (100 mL) and extracted twice with DCM (150 mL). The extracts are dried over Na 2 SO 4 and evaporated to give a crude E / Z mixture of {1 - [(1S, 5R) -6,6-dimethyl-3-oxo-bicyclo [3,1,1] hexylidene] ethyl sulfanyl} acetic acid (18.2 g) as a brown oil. LC-MS: t R = 1.00 min, [M + 1] + = 269.13. 1H NMR (CDCl3): δ 4.22 (q, J = 7.0 Hz 5 2H both isomers), 3.67 (d, J = 15.8 Hz, 1H largest isomer), 3.63 (d, J = 15.8 Hz, minor isomer IH), 3.58 (d, J = 15.8 Hz, larger isomer IH), 3.54 (d, J = 15.8 Hz, 1 H, minor isomer), 2, (Dd, J = 6.4, 19.4 Hz, 1H minor isomer), 2.60 (dd, J = 7.0, 19.4 Hz, 1H larger isomer), 2.58 (s, 3H isomer) minor), 2.52 (s, 3H larger isomer), 2.36-2.32 (m, 1H larger isomer), 2.30-2.26 (m, 1H larger isomer, 1H smaller isomer), 2, 18 (d, J = 7.0 Hz, 1H minor isomer), 2.00 (d, J = 7.0 Hz, 1H major isomer), 1.95 (d, J = 7.6 Hz, 1H minor isomer), 1.30 (t, J = 7.0 Hz, 3H larger isomer), 1.28 (t, J = 7.0 Hz, 3H smaller isomer), 1.18 (s, 3H larger isomer) 0.15 (s, 3H minor isomer), 0.89 (s, 3H minor isomer), 0.85 (s, 3H larger isomer).

b) A solution of Na (1.70 g, 74.8 mmol) in abs. HCl (75 mL) is heated to 60 ° C before being treated with a solution of {1 - [(1 S, 5R) -6,6-dimethyl-3-oxobicyclo [3,1.0] hex acid - (2Z) -ylidene] ethylsulfanyl} -acetic acid (18.2 g, 68.0 mmol) in ethanol abs. (200 mL). The mixture is stirred at 75 ° C for 20 min, then cooled to rt, diluted with aq. 0.5 M (500 mL) and extracted with DCM (450 + 200 mL). The combined extracts are dried over filtered Na 2 SO 4 and the solvent is removed in vacuo. This gives (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid ethyl ester crude oil (10.5 g) as a yellow oil of 87% purity (LC-MS, UV 280 nm). LC-MS: t R = 1.11 min, [M + 1] + = 251.14; 1H NMR (CDCl3): δ 4.26 (q, J = 7.0 Hz, 2H), 2.95 (dp, Jd = 18.8 Hz, Jp = 3.5 Hz, 1H), 2.79 ( d, J = 19.3, 1H), 2.37 (s, 3H), 1.89-1.84 (m, 2H), 1.34 (t, J = 7.0 Hz, 3H), 1 .12 (s, 3H), 0.72 (s, 3H).

(1S, 5aR) -1,2,2-Trimethyl-1α, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalene-4-carboxylic acid (Compound 2) <formula > formula see original document page 38 </formula>

In a solution of (la5,5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid ethyl ester NaHCO3 (10.3 g, 41.2 mmol) in ethanol (200 mL) aq. 2N (300 mL) is added. The resulting mixture is stirred at 70 ° C for 1 h, cooled to rt and diluted with water (250 mL). The solution aq. It is extracted three times with DCM (125 mL) before being acidulated to pH 3 by the addition of citric acid. The acidulated solution is extracted twice with DCM (2x250 mL). These second extracts are combined, dried over Na 2 SO 4, filtered and evaporated to leave (1α5.5aR) -1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa acid [ a] Pentalene-4-carboxylic acid (7.0 g) as a yellow solid.

LC-MS: t R = 0.95 min, [M + 1] + = 223.00. 1H NMR (CDCl3): δ 3.04-2.92 (m, 1H), 2.83 (d, J = 19.3 Hz, 1H), 2.39 (s, 3H), 1.91-1 , 87 (m, 2H), 1.13 (s, 3H), 0.73 (s, 3H).

Alternatively, (1α5,5aR) -1,2,2-trimethyl-1,1α, 5,5α-tetrahydro-3-thia-cyclo-propa [α] pentalene-4-carboxylic acid is also obtained by the following procedure. : In a solution of sodium (2.80 g, 122 mmol) in ethanol (400 mL) a solution of mercaptoacetic acid ethyl ester (14.64 g, 122 mmol) in ethanol (40 mL) is added. The solution is stirred for 5 min before (15.5R) -2- (1-chloro- (E) -ethylidene) -6,6-dimethyl-bicyclo [3,1.0] hexan-3-one (15 0.1 g, 81.2 mmol) in ethanol (40 mL) is added dropwise. The solution becomes slightly hot (approx. 30 ° C) and changes from orange to brown. A fine precipitate is formed. Agitation is continued at rt for 1 h. Then a solution of sodium (2.24 g, 97.5 mmol) in ethanol (75 mL) is added rapidly and the mixture is heated to 75 ° C for 1 h. A solution aq. 2N LiOH (75 mL) is added and stirring is continued at 75 ° C for 2 h, then at rt for 16 h. About 2/3 of the solvent is removed in vacuo, the remaining mixture is diluted with water (250 mL) and extracted with DCM (200 mL). The organic extract is washed twice with 1 N aq. [sic] (100 mL). The combined aqueous layers are acidified by the addition of aq. 2N and extracted three times with diethyl ether (3x300 mL). The organic extracts are dried over MgSO4 and evaporated. The remaining residue is suspended in acetonitrile, filtered, washed with additional acetonitrile and dried under high vacuum to give the title compound (12.02 g) as a pale yellow to beige crystalline powder.

rac- (1S, 5R) -2- [1-Chloro-et- (E) -ylidene] -6,6-dimethyl-bicyclo [3,1,0] hexan-3-one (Compound 7)

<formula> formula see original document page 39 </formula>

a) To a suspension of (+) -3-carene (82 g, 0.6 mol) and CaCO3 (80 g, 0.8 mol) in water (300 mL) and dioxane (600 mL) is added N-bromo - succinimide (142 g, 0.8 mol). The mixture is stirred at rt for 1 h, diluted with water (1500 mL) and extracted with diethyl ether (500 mL). The organic extract is washed with water (3x1000 mL) and aq. NaHCO 3 (2x500 mL), and dried over Na 2 SO 4. The solvent is removed under reduced pressure and the crude product is purified by silica gel column chromatography eluting with 4: 1 hexane / EA to give (1S, 3R, 4R, 6R) -4-bromo-3,7,7 -trimethyl-bicyclo [4,1.0] heptan-3-ol (48.3 g) as a beige solid. 1H NMR (CDCl3): δ 4.05 (dd, J = 7.6, 10.6 Hz, 1H), 2.48-2.36 (m, 2H), 2.20 (dd, J = 10, 0.14.7 Hz, 1H), 1.42-1.38 (m, 1H), 1.36 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.90-0.80 (m, 1H), 0.72-0.66 (m, 1H). b) In a solution of (1S, 3R, 4R, 6R) -4-bromo-3,7,7-trimethyl-bicyclo [4,1,0] heptan-3-ol (58.0 g, 0.25 mol) in water (120 mL) and dioxane and (1600 mL) is added Ag 2 O (156.4 g, 0.675 mol). The resulting suspension is stirred at rt for 18 h before being filtered over celite. The filtrate is evaporated under reduced pressure. The remaining solid is dissolved in diethyl ether (650 mL) and washed with water (2x 1000 mL). The organic extract is dried over Na 2 SO 4 and the solvent removed in vacuo to give 1 - ((1S, 3S, 5R) -6,6-dimethyl-bicyclo [3,1.0] hex-3-yl) -ethanone ( 36.6 g) as a pale yellow oil. 1H NMR (CDCl3): δ 2.83-2.70 (m, 1H), 2.14-2.03 (m, 5H), 1.82 (dd, J = 10.0, 14.1 Hz, 2H), 1.16-1.13 (m, 2H), 0.95 (s, 6H).

c) In a solution of 1 - ((1S, 3S, 5R) -6,6-dimethyl-bicyclo [3,1.0] hex-3-yl) -ethanone (36.5 g, 0.24 mol) In DCM (700 mL) 70% m-chloro-perbenzoic acid (77 g, 0.312 mol) is added portionwise. The reaction mixture is stirred at rt for 36 h before being washed with sat. Aq. 0.2 N (1000 mL). The wash solution is back extracted with DCM (2x300 mL). The combined organic extracts are dried over MgSO4 and the solvent removed in vacuo to give acetic acid (1S, 3S, 5R) -6,6-dimethyl-bicyclo [3,1,0] hex-3-yl ester ( 37.8 g) as a pale yellow oil. 1H NMR (CDCl3): δ 4.94 (hept. J = 3.5 Hz, 1H), 2.02-1.93 (m, 5H), 1.87-1.78 (m, 2H), 1 , 22-1.15 (m, 2H), 0.95 (s, 3H), 0.83 (s, 3H).

d) A solution of acetic acid (1S, 3S, 5R) -6,6-dimethyl-bicyclo [3,1.0] hex-3-yl ester (37.85 g, 225 mmol) in ethanol (700 mL) is treated with aq. 2 N (700 mL). The mixture is stirred at rt for 1 h, diluted with water (600 mL) and extracted with EA (2x150 mL). The combined organic extracts are dried over MgSO4 and evaporated to give (1S, 3S, 5R) -6,6-dimethyl-bicyclo [3,1.0] hexan-3-ol (23.9 g) as a pale yellow oil . 1H NMR (CDCl3): δ 4.23 (hept, J = 2.9 Hz, 1H), 1.87-1.70 (m, 4H), 1.23-1.20 (m, 2H), 0 , 96 (s, 3H), 0.81 (s, 3H).

e) In a mixture of pyridine (80 mL) and DCM (720 mL) is added C1O3 (50 g, 0.5 mol). The mixture is stirred for 5 min before (1S, 3S, 5R) -6,6-dimethyl-bicyclo [3,1.0] hexan-3-ol (11.5 g, 0.08 mol) is added. Agitation is continued at rt for 2.5 h. The mixture is decanted from an oily residue, diluted with DCM (100 mL) and washed with sat. Aq. 2 N (3x80 mL) followed by aq. sat. NaHCO3 (80 mL). The separated organic phase is dried over NaSO 4 and the solvent is removed in vacuo to afford (1S, 5R) -6,6-dimethyl-bicyclo [3,1.0] hexan-3-one as a pale yellow oil. 1H NMR (CDCl3): δ 2.58-2.46 (m, 2H), 2.19-2.11 (m, 2H), 1.34-1.26 (m, 2H), 1.09 ( s, 3H), 0.87 (s, 3H).

f) In a suspension of NaH (873 mg of 55% dispersion in mineral oil, 20 mmol, washed with dioxane and before use) in dioxane (15 mL) is added methyl acetate (2.22 g, 30 mmol). The suspension is stirred for 5 min at rt and a solution of (1S, 5R) -6,6-dimethyl-bicyclo [3,1.0] hexan-3-one (1.24 g, 10 mmol) in dioxane and (5 mL) is added. The reaction mixture is stirred at 65 ° C overnight. The mixture is poured over aq. 10% citric acid solution (75 mL) and extracted with DCM (3x75 mL). The organic extracts are washed with water, dried over MgSO4 and evaporated to give racemic (1R, 2R, 5R) -2-acetyl-6,6-dimethyl-bicyclo [3,1.0] hexan-3-one crude (2.45 g, contains dioxane) as a dark yellow liquid. 1H NMR (CDCl3): δ 2.61 (dd, J = 7.3, 19.6 Hz, 1H), 2.34-2.20 (m, 1H), 2.01 (s, 3H), 1 72 (d, J = 8.2 Hz, 1H), 1.40-1.20 (m, 2H), 1.09 (s, 3H), 0.81 (s, 3H).

g) A mixture of the above yellow liquid (1.66 g, 10 mmol), triphenyl phosphine (4.53 g, 17 mmol) and CC14 (5 mL) in chloroform (15 mL) is heated to 65 ° C for 1 min. H. The mixture is concentrated and the remaining residue is stirred with pentane. The pentane is decanted and the remaining residue is once again treated with pentane. The pentane fractions are combined and concentrated to leave rac- (1S, 5R) -2- [1-chloro-et- (E) -ylidene] -6,6-dimethyl-bicyclo [3,1,0] hexanes. 3-one (1.9 g) as brownish oil. This material is used in the next step without further purification. LC-MS: t R = 1.02 min. (1 aS, 5aR) -1,1,2-Trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carbonitrile (Compound 11)

<formula> formula see original document page 42 </formula>

A solution of (1S, 5R) -2- (1-chloro- (E) -ethylidene) -6,6-dimethyl-bicyclo [3,1.0] hexan-3-one (997 mg, 5.40 mmol ) and thioacetic acid S-cyano-methyl ester (746 mg, 6.48 mmol) in THF (37 mL) is treated with aq. 2 N (10.8 mL). The resulting mixture is stirred vigorously at rt for 2 h. Another portion of thioacetic acid S-cyano-methyl ester (100 mg, 0.87 mmol) and aq. 2 N (2 mL) is added and stirring is continued for 1 h. The reaction mixture is diluted with aq. 2 N and extracted twice with DCM. The organic extracts are dried over Na 2 SO 4 and evaporated. The remaining brown oil is dissolved in THF (30 mL) and treated with sat. Aq. 2 N (3 mL). The mixture is heated to 90 ° C for 4 h before being diluted with aq. 2 N and extracted with DCM. The organic extracts are dried over Na 2 SO 4 and evaporated. The crude product is purified by prep. HPLC. (Phenomenex Aqua 30mm x75mm, gradient 10% to 95% acetonitrile in water containing 0.5% formic acid) to give (laS, 5aR) -1,2-trimethyl-1,1a, 5, 5a-tetrahydro-3-thia-cyclo-propa [a] pentalene-4-carbonitrile (650 mg) as a brown oil; LC-MS: t R = 1.06 min, [M + 1 + CH 3 CN] + = 245.11; 1H NMR (CDCl3): δ 2.90 (dd, J = 5.9, 18.8 Hz, 1H), 2.68 (d, J = 18.8 Hz, 1H), 2.38 (s, 3H ), 1.96-1.88 (m, 2H), 1.13 (s, 3H), 0.72 (s, 3H).

(1aS, 5aR) -N-Hydroxy-1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxamidine (Compound of Structure 9) <formula> formula see original document page 43 </formula>

In a stirred suspension of K tert-butylate (281 mg, 2.5 mmol), hydroxylamine hydrochloride (208 mg, 3.0 mmol) in methanol (4 mL) is added (1 aS, 5aR) -1. 1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carbonitrile (203 mg, 1.0 mmol). The reaction mixture is stirred at rt for 5 h before it is filtered. The filtrate is purified by prep. (Water XTerrra Prep MS C18 30 mm χ 75 mm, 10% to 95% acetonitrile in water containing 0.5% sat. Aq. NH3) to give (1aS, 5aR) -N-hydroxy-1,1,2 -trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropoprop [α] pentalene-4-carboxamidine (200 mg) as a colorless solid; LC-MS: t R = 0.72 min, [M + 1] + = 237.09.

Methanesulfonic acid 2,2-Dimethyl- [1,3] dioxan-5-yl-methyl ester

<formula> formula see original document page 43 </formula>

The title compound is prepared following the procedures given in B. Xu, A. Stephens, G. Kirschenheuter, A. F. Greslin, X. Cheng, J. Sennelo, M. Cattaneo, M. L. Zighetti, A. Chen, S.-A. Kim, H. S. Kim, N. Bischofberger, G. Cook, K. A. Jacobson, J. Med. Chem. 45 (2002) 5694-5709.

Example 1 <formula> formula see original document page 44 </formula>

(a) A mixture of 2,4-dimethoxy-benzonitrile (3.25 g, 20 mmol), hydroxylamine hydrochloride (2.92 g, 42 mmol) and K2CO3 (5.80 g, 42 mmol) in ethanol ( 80 mL) is stirred at 85 ° C for 27 h before being poured into water (250 mL). The solution is acidulated by the addition of aq. 1 N (75 mL) and extracted once with DCM (100 mL). The aq layer. is basified with aq. 1 N (90 mL) and extracted three times with DCM (3x150 mL). The organic extracts are dried over MgSO4, the solvent is evaporated and the residue is dried under high vacuum to leave N-hydroxy-2,4-dimethoxy-benzamidine (1.35 g) as a beige solid. LC-MS: t R = 0.68 min, [M + 1] + = 197.11.

b) A mixture of N-hydroxy-2,4-dimethoxy-benzamidine (98 mg, 0.50 mmol), (1S, 5aR) -1,2,2-trimethyl-1,1,5,5-tetra acid -hydro-3-thia-cyclo-propa [a] pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (178 mg, 0.55 mmol) and DIPEA (646 mg, 5 mmol) in DMF ( 4 mL) is stirred at rt for 45 min, then at 0 ° C for 1 h. The reaction mixture is directly subjected to prep HPLC purification. (Phenomenex Aqua 75x30 mm, acetonitrile / water gradient containing 0.5% formic acid) to give 3- (2,4-dimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [α] pentalen-4-yl) - [1,2,4] oxadiazole (19 mg) as a colorless lyophilisate; LC-MS: t R = 1.17 min, [M + 1] + = 383.13; 1H NMR (CDCl3): δ 7.89 (d, J = 8.8 Hz, 1H), 6.46 (dd, J = 2.3, 8.8 Hz, 1 H), 6.43 (d, J = 2.3 Hz, 1 H), 3.83 (s, 3H), 3.74 (s, 3H), 2.96 (dd, J = 5.9, 18.8 Hz, 1H), 2 80 (d, J = 18.8 Hz, 1H), 2.29 (s, 3H), 1.88-1.78 (m, 2H), 1.02 (s, 3H), 0.63 ( s, 3H).

Example 2 <formula> formula see original document page 45 </formula>

a) In dry methanol (285 mL) is carefully added tert-butyl K (28.28 g, 252 mmol) followed by hydroxylamine hydrochloride (15.0 g, 216 mmol). The suspension is stirred for 30 min before 4-hydroxy-benzonitrile (8.58 g, 72 mmol) is added. The mixture is refluxed for 40 h, the solvent is evaporated and the residue is acidified by the addition of aq. 2 Ν. The solution is extracted twice with DCM (100 mL). The aq layer. is basified by the addition of solid NaHCOs. The product precipitates, is filtered, washed with water and dried to give 4,1 N-dihydroxy benzamidine (7.6 g) as a brownish solid; 1H NMR (D6-DMSO): δ 9.57 (s, 1 H), 9.33 (s, 1 H), 7.48-7.42 (m, 2H), 6.74-6.68 ( m, 2H), 5.62 (s, 2H).

(b) a solution of (1Î ± 5aR) -1,2,2-trimethyl-1Î ± 1Î ±, 5,5-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid (3, 50 g, 15.74 mmol), TBTU (5.56 g, 17.32 mmol) and DIPEA (8.89 mL, 51.96 mmol) in DMF (35 mL) is stirred for 10 min at rt before 4 ° C. N-dihydroxy benzamidine (2.64 g, 17.32 mmol) is added. The solution is stirred for a further 30 min, formic acid (7 mL) is added and the solution is chromatographed by prep HPLC. (Grom-Sil 120 ODS-4-HE, 30mm x75mm, gradient with acetonitrile / water containing 0.5% formic acid) to give N- (4-hydroxy- (hydroxybenzamidine)) - acid ester ( laS, 5aR) -1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid (4.5 g) as a colorless solid LC-MS: t R = 0.97 min, [M + 1] + = 357.14.

c) A solution of (1 aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydroxy acid N- (N-hydroxy-4-hydroxy-benzamidine) -esterester 3-thia-cyclopropa [a] pentalene-4-carboxylic acid (4.5 g, 12.63 mmol) in toluene (450 mL) is stirred at 105 ° C for 48 h before the solvent is removed under reduced pressure. . The residue is dissolved in acetonitrile / methanol and purified by prep. (Grom-Sil 120 ODS-4-HE, 30 mm χ 75 mm, gradient with acetonitrile / water containing 0.5% formic acid) to give 4- [5 - ((laS, 5aR) - 1.1.2 -trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) -

[1,2,4] oxadiazol-3-yl] -phenol (2.9 g) as a colorless solid; LC-MS: t R = 1.11 min, [M + 1] + = 339.13; 1H NMR (CDCl3): δ 8.04-7.98 (m, 2H), 6.94-6.89 (m, 2H), 5.37 (s br, 1H), 3.10 (dd, J = 5.7, 18.8 Hz, 1H), 2.93 (d, J = 18.8 Hz, 1H), 2.43 (s, 3H), 2.00-1.92 (m, 2H) 1.14 (s, 3H), 0.75 (s, 3H).

Examples 3 to 12

tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenol (10 mg, 0.03 mmol) in isopropanol (1 mL ) the corresponding alkylating agent (such as bromide, chloride or mesylate) (0.15 mmol) and aq. 2 N (0.2 mL) is added. The reaction mixture is stirred for 8 h at 70 ° C. Reaction mixtures are purified by prep. (either Waters XTerra Prep MS Cl8 19 mm x 50 mm 5 μιη, 90% to 5% water (0.8% NEt2) / acetonitrile or Waters SymmetryCl8 19 mm χ 50 mm 5 μπι, 90% to 5% water ( 0.5% HCOOH) / acetonitrile) to give the desired products as colorless lyophilisates. In the case of Example 8 the reaction mixture is stirred for 8 h at 85 ° C before TFA (0.3 mL) is added. The mixture is stirred for another hour at 60 ° C prior to prep. HPLC purification.

In a solution of 4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1, la, 5,5a <table> table see original document page 47 </column> </row> < table>

Example 13

<formula> formula see original document page 47 </formula>

a) In dry methanol (190 mL) is carefully added K tert-butylate (18.68 g, 166 mmol) followed by hydroxylamine hydrochloride (9.92 g, 143 mmol). The suspension is stirred for 30 min before 3,5-dimethyl-4-hydroxy-benzonitrile (7.00 g, 147 mmol) is added. The mixture is refluxed for 32 h, then the suspension is diluted by the addition of aq. 2 Ν. The solution is extracted twice with DCM (100 mL). The aq layer. It is basified (pH 9) by the addition of solid NaHCO3 and extracted five times with DCM followed by four times with EA. The combined organic layers are dried over Na 2 SO 4 and evaporated to dryness to give 4,1 N-dihydroxy-3,5-dimethyl benzamidine (7.9 g) as a colorless solid; LC-MS: t R = 0.62 min, [M + 1] + = 181.14.

(b) a solution of (1Î ± 5aR) -1,2,2-trimethyl-1Î ± 1Î ±, 5,5-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid (3, 00 g, 13.50 mmol), TBTU (4.77 g, 14.85 mmol) and DIPEA (7.62 mL, 44.53 mmol) in DMF (30 mL) is stirred for 10 min at rt before 4 ° C. N-dihydroxy-3,5-dimethyl benzamidine (2.68 g, 14.85 mmol) is added. The solution is stirred for a further 20 min, formic acid (6 mL) is added and the solution is chromatographed by prep HPLC. (Grom-Sil 120 ODS-4-HE, 30 mm χ 75 mm, gradient acetonitrile / water containing 0.5% formic acid) to give N- (3,5-dimethyl-4-hydroxy-N-hydroxy). (laS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid benzamidine) ester (4, 1 g) as a colorless solid; LC-MS: t R = 1.03 min, [M + 1] + = 385.18; 1H NMR (D6-DMSO): δ 8.65 (s, 1H), 7.30 (s, 2H), 6.38 (s br, 2H), 3.04 (dd, J = 5.9, 18 , 8 Hz, 1H), 2.75 (d, J = 18.8 Hz, 1H), 2.36 (s, 3H), 2.18 (s, 6H), 2.01-1.88 (m , 2H), 1.10 (s, 3H), 0.70 (s, 3H).

c) A suspension of (1S, 5aR) -1,2,2-trimethyl-1,2,5-α-acid N- (3,5-dimethyl-4-hydroxy-N-hydroxy-benzamidine) -esterester tetrahydro-3-thia-cyclo-propa [a] pentalene-4-carboxylic acid (4.0 g, 10.41 mmol) in toluene (400 mL) is stirred at 100 ° C for 24 h before the solvent is removed. removed under reduced pressure. The residue is dissolved in DCM and purified by silica gel column chromatography eluting with hexane: EA 5: 1 to give 2,6-dimethyl-4- [5 - ((laS, 5aR) -1,1,2- trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenol (1, 5 g) as a colorless solid; LC-MS: t R = 1.37 min, [M + 1] + = 367.13; 1H NMR (CDCl3): δ 7.75 (s, 2H), 4.90 (s, 1H), 3.12 (dd, J = 5.9, 18.8 Hz, 1H), 2.94 (d , J = 18.8 Hz, 1H), 2.44 (s, 3H), 2.32 (s, 6H), 2.02-1.94 (m, 2H), 1.16 (s, 3H) 0.77 (s, 3H).

Examples 14 to 18 and 20 to 23

<formula> formula see original document page 49 </formula>

In a solution of 2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [ a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] phenol (10 mg, 0.027 mmol) in isopropanol (1 mL) the corresponding alkylating agent (such as bromide, chloride or mesylate) ( 0.135 mmol) and aq. 2 N (0.2 mL) is added. The reaction mixture is stirred for 10h at 65 ° C. Reaction mixtures are purified by prep. (Waters XTerra Prep MS Cl8 19mm χ 50mm, 5μηι, 80% to 5% water (0.85% NEt2) / Acetonitrile) to give desired products as colorless lyophilisates

<formula> formula see original document page 49 </formula> <table> table see original document page 50 </column> </row> <table>

Example 14

1H NMR (CDCl3): δ 7.78 (s, 2H), 4.00-3.90 (m, 4H), 3.12 (dd, J = 5.9, 18.8 Hz, 1H), 2 94 (d, J = 18.8 Hz, 1H), 2.43 (s, 3H), 2.36 (s, 6H), 2.14 (t br, J = 5 Hz, 1H), 2, 01-1.92 (m, 2H), 1.15 (s, 3H), 0.76 (s, 3H).

Example 16

1H NMR (CDCl3): δ 7.78 (s, 2H), 4.17-4.08 (m, 1 H), 3.94-3.80 (m, 4H), 3.11 (dd, J = 5.9, 18.8 Hz, 1H), 2.94 (d, J = 18.8 Hz, 1H), 2.72 (d br, J = 3.5 Hz, 1H), 2.43 ( s, 3H), 2.35 (s, 6H), 2.06 (s br, 1H), 2.01-1.90 (m, 2H), 1.14 (s, 3H), 0.76 (s, 3H).

Example 20

1H NMR (CDCl3): δ 7.78 (s, 2H), 4.01-3.92 (m, 4H), 3.11 (dd, J = 5.9, 18.8 Hz, 1H), 2 94 (d, J = 18.8 Hz, 1H), 2.43 (s, 3H), 2.35 (s, 6H), 2.14-2.03 (m, 2H), 2.00- 1.91 (m, 3H), 1.15 (s, 3H), 0.76 (s, 3H).

Example 19

<formula> formula see original document page 50 </formula>

a) In a solution of triphenyl phosphine (161 mg, 0.615 mmol) in dry THF is added DEAD (0.097 mL, 0.615 mmol). The solution is stirred at rt for 1 h before (2,2-dimethyl- [1,3] dioxan-5-yl) methanol (90 mg, 0.615 mmol) and 2,6-dimethyl-4- [5- ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4 ] oxadiazol-3-yl] -phenol (150 mg, 0.410 mmol) are added. Agitation is continued for 24 h. The reaction mixture is purified by prep HPLC. (Waters XTerra Prep MS Cl8 19 mm χ 50 mm, 5 μm, water (0.85% NEt2) / acetonitrile) to give 3- [4- (2,2-dimethyl- [1,3] dioxan-5- ylmethoxy) -3,5-dimethyl-phenyl] -5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] pentalen-4-yl) - [1,2,4] oxadiazole (135 mg) as colorless lyophilisate; LC-MS: t R = 1.29 min, [M + 1] + = 495.30.

b) A suspension of 3- [4- (2,2-dimethyl- [1,3] dioxan-5-ylmethoxy) -3,5-dimethylphenyl] -5 - ((1 aS, 5 aR) -1,1,2-trimethyl-1,1α, 5,5α-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazole (135 mg, 0.273 mmol) in 4: 1 acetic acid / water (4 mL) and THF (2 mL) is stirred at rt for 3 h. So, HCl approx. 6 N in isopropanol (1 mL) is added and stirring is continued for 30 min. Diethylamine (0.2 mL) is added in a mixture which is then purified by prep. HPLC. (Grom-Sil 120 ODS-4-HE, 30 mm x 75 mm, 10 μm, acetonitrile / water (0.5% HCOOH), 20% to 95% acetonitrile) to give 2- {2,6-dimethyl- 4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl ) - [1,2,4] oxadiazol-3-yl] -phenoxy-methyl} -propane-1,3-diol (50 mg) as a colorless resin; LC-MS: t R = 1.12 min, [M + 1] + = 455.22;

1H NMR (CDCl3): δ 7.78 (s, 2H), 4.05-4.00 (m, 4H), 3.98-3.94 (m, 2H), 3.11 (dd, J = 6.4, 18.8 Hz, 1H), 2.94 (d, J = 18.8 Hz, 1H), 2.43 (s, 3H), 2.35 (s, 6H), 2.32- 2.23 (m, 1H), 2.14 (s br, 2H), 2.00-1.92 (m, 2H), 1.15 (s, 3H), 0.76 (s, 3H).

Examples 24 to 34, 36 and 37 <formula> formula see original document page 52 </formula>

a) In a solution of 2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclo -prop ([a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenol (250 mg, 0.68 mmol) in isopropanol (6.8 mL) and aq. 2 N (2.3 mL) 3-bromoethanol (0.12 mL, 1.42 mmol) is added.

The reaction mixture is stirred for 13 h at 65 ° C. The solution is poured over aq. 0.5 N and extracted twice with DCM. The organic extracts are dried over MgSO4 and evaporated. The crude product is purified by silica gel column chromatography eluting with 22: 1 DCMrTBME to give 3- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl -1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-1-one 1-ol (170 mg, Example 20) as a beige resin; LC-MS: t R = 1.20 min, [M + 1] + = 425.20.

(b) at 0 ° C, a solution of 3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1α, 5,5a-tetrahydro- 3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-1-ol (170 mg, 0.40 mmol) and DIPEA (0.11 mL, 0.64 mmol) in DCM (5 mL) is treated with methanesulfonyl chloride (0.04 mL, 0.48 mmol). The reaction mixture is stirred at 0 ° C for 30 min, then at rt for 1 h before being diluted with DCM (15 mL) and washed with sat. Aq. 0.1 N (20 mL) followed by aq. 10% citric acid (20 mL). The organic layer is dried over Na 2 SO 4 and evaporated to dryness to give 3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5 to methanesulfonic acid-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl ester (185 mg ) as a beige resin; LC-MS: t R = 1.23 min, [M + 1] + = 503.20. c) A mixture of 3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo] -propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl ester of methanesulfonic acid (9 mg, 0.017 mmol), the corresponding amine (0.067 mmol) and DIPEA (0.025 mL) in DMF is stirred at 85 ° C for 7 h. The reaction mixture is subjected to prep HPLC purification. (Waters Xterra MS18 19 mm χ 50 mm 5 pm, 90% to 5% 0.1 N aq. HCl / acetonitrile) to give the desired products as colorless lyophilisates.

<table> table see original document page 53 </column> </row> <table> Example 27 (as hydrochloride)

1H NMR (D6-DMSO): δ 8.81 (s br, 2H), 7.67 (s, 2H), 5.25 (t br, J = 5 Hz, 1H), 3.88 (t, J = 5.9 Hz, 2H), 3.71-3.64 (m, 2H), 3.20-3.00 (m, 5H), 2.84 (d, J = 18.8 Hz, 1H) 2.41 (s, 3H), 2.30 (s, 6H), 2.18-1.96 (m, 4H), 1.10 (s, 3H), 0.70 (s, 3H).

Example 35

<formula> formula see original document page 54 </formula>

a) In a solution of triphenyl phosphine (161 mg, 0.615 mmol) in Dry THF (2.5 mL) is added DEAD (0.097 mL, 0.615 mmol). The solution is stirred at rt for 1 h before (2,2-dimethyl-5-nitro- [1,3] dioxan-5-yl) methanol (118 mg, 0.615 mmol) and 2,6-dimethyl-4 - [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [ 1,2,4] oxadiazol-3-yl] phenol (150 mg, 0.410 mmol) are added. Agitation is continued for 7 days. The formed precipitate is collected, washed with isopropanol and dried under high vacuum to give 3- [4- (2,2-dimethyl-5-nitro- [1,3] dioxan-5-yl-methoxy) -3,5- dimethylphenyl] -5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-one il) - [1,2,4] oxadiazole (90 mg) as an almost colorless solid; LC-MS: t R = 1.30 min, [M + 1] + = 540.28; 1H NMR (CDCl3): δ 7.77 (s, 2H), 4.50 (d, J = 12.9 Hz, 2H), 4.29-4.21 (m, 4H), 3.10 (dd , J = 6.4, 18.8 Hz, 1H), 2.93 (d, J = 18.8 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 6H), 2 .00-1.91 (m, 2H), 1.48 (s, 3H), 1.45 (s, 3H), 1.15 (s, 3H), 0.76 (s, 3H).

b) A suspension of 3- [4- (2,2-dimethyl-5-nitro- [1,3] dioxan-5-yl-methoxy) -3,5-dimethyl-phenyl] -5 - ((1 aS , 5 aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4 ] oxadiazole (85 mg, 0.158 mmol) in 20: 4: 1 THF: TFA: water (12.5 mL) is stirred at 65 ° C for 4.5 h. The mixture is further diluted with 2: 1 TFA water (1.5 mL) and stirring is continued at 65 ° C for 3 h. The mixture is cooled to rt, poured over aq. 2 N and extracted twice with DCM. The organic extracts are dried over MgSO4 and evaporated to give 2- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydrochloride). hydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxymethyl} -2-nitro-propane-1,3-diol ( 78 mg) as a beige resin; LC-MS: t R = 1.17 min, [M + 1] + = 500.89.

c) A solution of 2- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thiadiazepine) cyclopropa [a] pentalen-4-yl- [1,2,4] oxadiazol-3-yl] -phenoxy-methyl} -2-nitro-propane-1,3-diol (75 mg, 0.151 mmol) in acetonitrile (9 mL), TFA (4 mL) and water (0.5 mL) are treated with Zn (200 mg, 3.06 mmol) The suspension is stirred at 65 ° C for 1 h before another portion of Zn (100 mg, 1.53 mmol) is added Stirring is continued at 65 ° C for 45 min The mixture is filtered and the filtrate is poured into 2 N aq NaOH and extracted three times with DCM The organic extracts are dried over MgSO 4 and evaporated The crude product is purified by prep HPLC (Water Symmetry C18, 19 mm χ 50 mm, 95% water gradient (0.5% formic acid) to 95% acetonitrile) to give 2% hydrochloride. -amino-2- {2,6-dimethyl-4- [5- ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-2-one cyclopropa [a] pentalen-4-yl- [1,2,4] oxadiazol-3-yl] -phenoxy-methyl} -propane-1,3-diol (23 mg) as a colorless powder after evaporation product isolated from a mixture of methanol (9 mL) and 6 N HCl in isopropanol (1 mL); LC-MS: t R = 0.89 min, [M + 1] + = 470.26; 1H NMR (D6-DMSO): δ 8.18 (s br, 3H), 7.69 (s, 2H), 5.47 (s br, 2H), 3.87 (s, 2H), 3.71 (s, 4H), 3.07 (dd, J = 5.9, 18.8 Hz, 1H), 2.84 (d, J = 18.8 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 6H), 2.08-1.97 (m, 2H), 1.11 (s, 3H), 0.70 (s, 3H).

Example 38 <formula> formula see original document page 56 </formula>

a) In a solution of 3,5-dimethyl-4-hydroxy benzoic acid (158 mg, 0.95 mmol), TBTU (305 mg, 0.95 mmol), DIPEA (0.49 mL, 2.85 mmol) in DMF (2.5 mL) is added (1αS, 5aR) -N-hydroxy-1,2,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a ] pentalene-4-carboxamidine (200 mg, 0.852 mmol) in DMF (3.5 mL). The resulting suspension is stirred at rt for 2 h. Another portion of 3,5-dimethyl-4-hydroxy-benzoic acid (158 mg, 0.95 mmol), TBTU (305 mg, 0.95 mmol) and DIPEA (0.49 mL, 2.85 mmol) is added. and stirring is continued for another 30 min. The reaction mixture is directly purified by prep. (Phenomenex Aqua 30 mm x 75 mm, 20% to 95% acetonitrile in water containing 0.5% formic acid) to give the hydroxy amidine ester intermediate (150 mg) as a colorless solid; LC-MS: t R = 1.04 min, [M + 1] + = 385.20.

b) A solution of hydroxy amidine ester (150 mg, 0.40 mmol) in toluene is stirred at 100 ° C for 35 h. The solvent is removed under reduced pressure and the residue is purified by prep. (Phenomenex Aqua 30mm x75mm, 20% to 95% acetonitrile in water containing 0.5% formic acid) to give 2,6-dimethyl-4- [3 - ((laS, 5aR) -1,2,2 -trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenol (125 mg ) as a colorless solid; LC-MS: t R = 1.19 min, [M + 1] + = 367.18; 1H NMR (CDCl3): δ 7.80 (s, 2H), 5.07 (s, 1H), 3.06 (dd, J = 5.9, 18.8 Hz, 1H), 2.89 (d , J = 18.8 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 6H), 1.98-1.90 (m, 2H), 1.15 (s, 3H) 0.78 (s, 3H). Examples 39 to 43 <formula> formula see original document page 57 </formula>

In a solution of ((1 aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] phenol (10 mg, 0.027 mmol) in isopropanol (1 mL), the corresponding alkylating agent (such as bromide, chloride or mesylate) (0.135 mmol) and aq. 2 N (0.2 mL) is added. The reaction mixture is stirred for 10 h at 65 ° C. Reaction mixtures are purified by prep. HPLC. (Waters XTerra Prep MS C18 19 mm χ 50 mm 5 μm, 80% to 5% water (0.85% NEt2) / Acetonitrile) to give the desired products as colorless lyophilisates.

In the case of Example 43, the reaction mixture is stirred for 10h at 80 ° C. To effect diol deprotection, the product obtained after purification is dissolved in 1 mL of 8: 2 CH 3 COOH / H 2 O and allowed to stand for 2 h at rt before being purified by prep HPLC. once again.

<formula> formula see original document page 57 </formula>

Example 44 <formula> formula see original document page 58 </formula>

(a) In an icy suspension of K tert-butylate (22.44 g, 200 mmol) and hydroxylamine hydrochloride (8.34 g, 120 mmol) in methanol (250 mL) 3-trifluoromethyl benzonitrile (6, 84 g, 40 mmol) is added. The mixture is refluxed for 2.5 h, the solvent is removed under reduced pressure and the residue is dissolved in water. The solution is extracted twice with EA. The organic extracts are dried over Na2 SO4, evaporated and dried under high vacuum to give N-hydroxy-3-trifluoromethyl benzamidine (8.1 g) as a white solid, LC-MS: t R = 0.54 min, [M + 1] + = 205.18.

(b) In a solution of (1S, 5aR) -1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalene-4-carboxylic acid ( 450 mg, 2.03 mmol), TBTU (715 mg, 2.23 mmol) and DIPEA (863 mg, 6.68 mmol) in DMF (7 mL) N-hydroxy-3-trifluoromethyl benzamidine (455 mg, 2 , 23 mmol) is added and the mixture is stirred for 1.5 h. Formic acid (1.2 mL) is added and the mixture is purified by prep. (Grom-Sil 120 ODS-4 HE, 30 mm χ 75 mm, 10 μπι, 20% to 95% acetonitrile in water containing 0.5% formic acid) to give N- (N-hydroxy-3-trifluoromethyl (benzamidine) - (laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid ester (520 mg) as a colorless lyophilisate; LC-MS: t R = 1.12 min, [M + 1] + = 409.20.

c) A solution of (1S, 5aR) -1,2,2-trimethyl-1,2,5-tetrahydro-3-acid N- (N-hydroxy-3-trifluoromethyl-benzamidine) -esterester thia-cyclopropa [a] pentalene-4-carboxylic acid (480 mg) in toluene is refluxed for 7 days before the solvent is removed under reduced pressure. The residue is purified by CC over silica gel eluting with DCM to give 3- (3-trifluoromethyl-phenyl) -5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1 a, 5, 5α-tetrahydro-3-thia-cyclopropa [Î ±] pentalen-4-yl) - [1,2,4] oxadiazole (360 mg) as a pale yellow solid; LC-MS: t R = 1.26 min, [M + 1] + = 391.2; 1H NMR (CDCl3): δ 8.39 (s, 1 H), 8.30 (d, J = 7.6 Hz, 1 H), 7.76 (d, J = 8.2 Hz, 1 H) , 7.61 (t, J = 7.6 Hz, 1H), 3.12 (dd, J = 6.4, 18.8 Hz, 1H), 2.95 (d, J = 18.8 Hz, 1H), 2.45 (s, 3H), 2.02-1.93 (m, 2H), 1.15 (s, 3H), 0.77 (s, 3H).

Example 45

<formula> formula see original document page 59 </formula>

a) In an ice-cold solution of H 2 SO 4 (150 mL) in water (250 mL) 2-ethyl-6-methyl aniline (15.0 g, 111 mmol) is added. The solution is treated with ice (150 g) before a solution of NaNO2 (10.7 g, 155 mmol) in water (150 mL) and ice (50 g) is added dropwise. The mixture is stirred at 0 ° C for 1 h. Aq. 50% (200 mL) is added and stirring is continued at rt for 18 h. The mixture is extracted with DCM. The organic extracts are dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with 9: 1 heptane: EA to give 2-ethyl-6-methylphenol (8.6 g) as a crimson oil; LC-MS: t R = 0.89 min; 1H NMR (CDCl3): δ 7.03-6.95 (m, 2H), 6.80 (t, J = 7.6 Hz, 1 H), 4.60 (s, 1 H), 2.64 (q, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H).

(b) A solution of 2-ethyl-6-methylphenol (8.40 g, 61.7 mmol) and hexamethylene tetraamine (12.97 g, 92.5 mmol) in acetic acid (60 mL) and water ( 14 mL) is heated to 115 ° C. The water is distilled at 117 ° C and collected with a Dean-Stark apparatus. Then the water separator is replaced by a reflux condenser and the mixture is refluxed for 3 h. The mixture is cooled to rt, diluted with water (100 mL) and extracted with EA. The organic extract is washed with sat. aq., dried over MgSO4 and evaporated. The remaining solid is dissolved in EA and treated with heptane to initiate crystallization. The solid material is collected and dried to give 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (3.13 g) as a colorless crystalline powder, 1H NMR (CDCl3): δ 9.83 (s, 1 H) 7.58-7.53 (m, 2H), 5.30 (s br, 1H), 2.69 (q, J = 7.6 Hz, 2H), 2.32 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H).

c) In an ice-cold solution of 5-ethyl-4-hydroxy-3-methylbenzaldehyde (10.0 g, 60.9 mmol) in DCM (50 mL) and pyridine (15 mL), trifluoromethanesulfonic anhydride (18 , 9 g, 67 mmol) is added over a period of 20 min. Upon completion of the addition, the ice bath is removed and the reaction is stirred for a further 2 h at rt. The mixture is diluted with DCM (150 mL), washed three times with water, dried over MgSO4, filtered and evaporated. The residue is purified by flash silica gel chromatography eluting with 9: 1 heptane: EA 9 to give trifluoromethanesulfonic acid 2-ethyl-4-formyl-6-methylphenyl ester (10.75 g) as an oil pale yellow; LC-MS: t R -1.07 min; 1H NMR (CDCl3): δ 9.98 (s, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 2.85 (q, J = 10.1 Hz, 2H), 2.48 (s, 3H), 1.30 (t, J = 10.2 Hz, 3H).

d) In a stirred solution of the above triflate (10.7 g, 36.1 mmol) in dry DMF (75 mL) triethylamine (7.3 g, 72.2 mmol), methyl acrylate (31.1) are sequentially added. g, 361 mmol), DPPP (819 mg, 1.99 mmol) and Pd (OAc) 2 (405 mg, 1.81 mmol) under nitrogen. The mixture is stirred at 115 ° C for 5 h, cooled to rt, diluted with diethyl ether (350 mL) and washed twice with aq. 1 N and once with solution aq. sat. of NaHCO3. The organic extract is dried over MgSO4, filtered and evaporated. The residue is purified by silica gel flash chromatography eluting with 19: 1 heptane: EA to give 3- (2-ethyl-4-formyl-6-methylphenyl) acrylic methyl ester (5.93 g) as a colorless liquid; LC-MS: t R = 0.99 min.

e) A suspension of 3- (2-ethyl-4-formyl-6-methylphenyl) -acrylic acid methyl ester (5.93g, 25.53mmol) in methanol (140ml) and aq. 2 N (45 mL) is stirred at rt for 1 h. Methanol is evaporated and the aqueous solution is extracted twice with DCM. The aq layer. is acidified with aq. 37%.

The precipitate that forms is collected, washed with water and dried. The product is further purified by recrystallization from EA (100 mL) to give 3- (2-ethyl-4-formyl-6-methyl-phenyl) -acrylic acid (4.2 g) as yellow crystals; LC-MS: t R = 0.87 min.

f) In a solution of 3- (2-ethyl-4-formyl-6-methylphenyl) acrylic acid (2.75 g, 12.6 mmol) and DIPEA (1.8 g, 13.8 mmol) in ethanol (80 mL) Pd / C (275 mg, 10% Pd, moistened with 50% water) is added. The mixture is stirred for 16 h at rt under 1 atm H2. The catalyst is filtered off and the filtrate is concentrated. The residue is dissolved in EA, washed with aq. 2 N followed by aq. 1 N and brine. The organic extract is dried over Na 2 SO 4, filtered and evaporated to give 3- (2-ethyl-4-hydroxymethyl-6-methylphenyl) propionic acid (2.8 g) as a white solid; LC-MS: t R = 0.76 min.

g) A solution of 3- (2-ethyl-4-hydroxymethyl-6-methylphenyl) propionic acid (2.8 g, 12.6 mmol) in acetic acid (50 mL) is treated with MnO2 ( 3.9 g, 45.4 mmol) and the resulting mixture is stirred at 80 ° C for 4 h. The mixture is filtered and the filtrate is concentrated. The crude product is purified by CC on silica gel eluting with DCM to give 3- (2-ethyl-4-formyl-6-methylphenyl) propionic acid (1.76 g) as a beige solid; LC-MS: t R = 0.86 min.

h) A solution of 3- (2-ethyl-4-formyl-6-methylphenyl) propionic acid (1.67 g, 7.58 mmol) and hydroxylamine hydrochloride (780 mg, 11.36 mmol ) in 1-methyl-2-pyrrolidone is heated to 80 ° C for 30 min in a microwave oven (300 W, active cooling during irradiation). The reaction mixture is diluted with diethyl ether and washed with water and brine. The organic extract is dried over filtered Na 2 SO 4 and evaporated to give 3- (4-cyano-2-ethyl-6-methyl-phenyl) -propionic acid (1.55 g) as a beige solid; LC-MS: t R = 0.89 min, 1H NMR (D6-DMSO): δ 12.25 (s, 1H), 7.45 (s, 2H), 2.91-2.84 (m, 2Η) , 2.67-2.59 (m, 2Η), 2.35-2.30 (m, 5Η), 1.14 (t, J = 7.6 Hz, 3Η). i) Potassium tert-Butoxide (2.71 g, 24.1 mmol) is carefully dissolved in methanol (25 mL). In this solution hydroxyl amine hydrochloride (1.44 g, 20.7 mmol) followed by 3- (4-cyano-2-ethyl-6-methylphenyl) -propionic acid (1.50 g, 6.90 mmol) ) dissolved in methanol (7.5 mL) are added. The mixture is refluxed for 8 h and the solvent is evaporated. The residue is dissolved in aq. 2 N and extracted with EA. The pH of the aq. is adjusted to pH 5 by the addition of sat. aq. and the mixture is extracted three times with EA. The combined organic extracts are dried over Na 2 SO 4, filtered, evaporated and dried to give 3- [2-ethyl-4- (N-hydroxycarbamimidoyl) -6-methylphenyl] propionic acid (1.4 g) as a white solid; LC-MS: t R = 0.60 min, [M + 1] + = 251.17.

(j) In a solution of (1S, 5aR) -1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalene-4-carboxylic acid ( 270 mg 1.22 mmol) in DMF (3 mL), TBTU (390 mg, 1.22 mmol) and DIPEA (518 mg,

4.0 mmol) are added. The reaction mixture is stirred at rt for 5 min before a solution of 3- [2-ethyl-4- (N-hydroxycarbamimidoyl) -6-methylphenyl] propionic acid (305 mg, 1.22 mmol) in DMF (2 ML) be added. Agitation is continued at rt for 1 h. The mixture is diluted with formic acid (0.5 mL) and acetonitrile (5 mL) and separated by prep. HPLC. (Grom-Sil 120 ODS-4-HE, 30 mm χ 75 mm, 10 μιη, 10% to 95% acetonitrile in water containing 0.5% formic acid) to give N- (3-ethyl-5-methyl (1S, 5aR) -1,2-trimethyl-4- (2-carboxyethyl) -N-hydroxy-benzamidine) ester

1.1 a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid (260 mg) as a white solid; LC-MS: t R = 1.05 min, [M + 1] + = 455.32. (k) a suspension of (1S, 5aR) -1,1-N- (3-ethyl-5-methyl-4- (2- (hydroxycarboxyethyl) -N-hydroxy-benzamidine) -esterester 2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalene-4-carboxylic acid (255 mg, 0.561 mmol) in toluene (10 mL) is heated to 85 ° C for 24 h, then at 105 ° C for 3 days The mixture is cooled to rt and the solvent is evaporated The residue is dissolved in DMF and separated by prep HPLC (Grom-Sil 120 ODS-4-HE, 30 mm χ 75 mm, 10 μm, 70-100% acetonitrile in water containing 0.5% formic acid) to give 3- {2-ethyl-6-methyl-4- [5- ((1 aS, 5aR) acid) -1,1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazole-3 yl] phenyl} propionic (150 mg) as a white crystalline solid; LC-MS: t R = 1.19 min, [M + 1] + = 437.28; 1H NMR (D6-DMSO): δ 12, 26 (s, 1H), 7.64 (s, 1H), 7.63 (s, 1H), 3.08 (dd, J = 6.4, 19.3 Hz, 1H), 2, 94-2.89 (m, 2H), 2.84 (d, J = 18.2 Hz, 1H), 2.69 (q, J = 7.6 Hz, 2H), 2.41 (s, 3H ), 2.39-2.33 (m, 5H), 2.0 Δ (d, J = 5.8 Hz, 1H), 1.99 (t, J = 5.8 Hz, 1H), 1.19 (t, J = 7.6 Hz, 3H), 1.11 ( s, 3H), 0.70 (s, 3H).

Examples 46 and 47

1,1,2-trimethyl-1,1α, 5,5-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] - phenyl} -propionic (9 mg, 20 μmol) in DMF (0.5 mL), TBTU (7 mg, 22 μmol) and DIPEA (9 mg, 66 μmol) are added. The mixture is stirred at rt for 5 min before the appropriate amine (100 μmol) is added. Agitation is continued at rt for 1 h. The mixture is treated with formic acid (25 μL), diluted with acetonitrile (0.5 mL) and separated by prep HPLC. (Waters SymmetryC 18 19 mm χ 50 mm 5 μm, 20-100% acetonitrile in water containing 0.5% formic acid) to give the desired amide as a colorless resin.

In a solution of 3- {2-ethyl-6-methyl-4 [5 - ((1aS, 5aR) - <table> table see original document page 64 </column> </row> <table>

Example 48: GTPyS Assay for Determining EC50 Values

GTPyS binding assays are performed in 96-well microtiter plates (Nunc, 442587) in a final volume of 200 µl using recombinant human SlP1 receptor expressing CHO cell membrane preparations. Assay conditions are 20 mM Hepes (Fluka, 54461), 100 mM NaCl (Fluka, 71378), 5 mM MgCl2 (Fluka, 63064), 0.1% BSA (Calbiochem, 126609), GDP 1 μΜ (Sigma, G- 7127), 2.5% DMSO (Fluka, 41644), 50 pM 35S-GTPyS (Amersham Biosciences, SJ1320). The pH is 7.4. Test compounds are dissolved and diluted in DMSO100% and preincubated at room temperature for 30 min at 150 μl. above assay buffer in the absence of 35S-GTPyS. After 50 μ dilution of 35S-GTPyS, the assay is incubated for 1 h at room temperature. The assay is terminated by transferring the reaction mixture to a Multiscreen plate (Millipore, MAHFC1H60) using a Packard Biosciences cell harvester, and the plates are washed with cold, dry, sealed, 10mM Na2HPO4ZNaH2PO4 (70% / 30%). bottom and after addition of 25 μΕ MicroScint20 (Packard Biosciences, order no. 6013621), sealed at the top. Membrane-bound 5S-GTPyS is measured with a Packard Biosciences TopCount.

EC50 is the concentration of agonist inducing 50% of the maximum specific 35S-GTPyS binding. Specific binding is determined by subtracting non-specific binding from maximum binding. Maximum connection is the amount of cpm connected to the Multiscreen card in the presence of 10 μΜ S IP. Non-specific binding is the amount of binding in the absence of an agonist in the assay.

Table 1 shows the EC 50 values of some compounds of the present invention. EC 50 values were determined according to the method described above.

Table 1:

<table> table see original document page 65 </column> </row> <table>

Example 49: In vivo efficacy assessment

The efficacy of the compounds of Formula (I) is assessed by measuring circulating lymphocytes following oral administration of 3 to 30 mg / kg of a compound of Formula (I) to male Wistar normotensive rats. The animals are housed in climate controlled conditions with a 12 h light / dark cycle, and have free access to normal rat chow and drinking water. Blood is collected before and 3, 6 and 24 h after drug administration. Whole blood is submitted to hematology using the Advia Hematology system (Bayer Diagnostics, Zürich, Switzerland).

All data are presented as mean ± SEM. Statistical analyzes are performed by analysis of variance (ANOVA) using Statistica (StatSoft) and the Student-Newman-Keuls procedure for multiple comparisons. The null hypothesis is rejected when ρ <0.05.

As an example, Table 2 shows the effect on lymphocyte counts 6 h after oral administration of 10 mg / kg of two compounds of the present invention to male Wistar normotensive rats compared to a group of vehicle-treated animals only.

Table 2:

<table> table see original document page 65 </column> </row> <table>

Claims (16)

A compound, characterized in that it is selected from the group consisting of thiophenes of Formula (I) wherein ring A represents R1 represents hydrogen, C1-5-alkyl, C1- 5-alkoxy or halogen; R2 represents hydrogen, C1-5-alkyl, C1-5-alkoxy, trifluoromethyl, trifluoromethoxy, or halogen; R3 represents hydrogen, hydroxy-C10-alkyl, 2,3-dihydroxypropyl, di (hydroxy-C1-5-alkyl) -C1-5-alkyl, -CH2- (CH2) k-NR31R32, (acid azetidine-3-carboxylic acid) -1-ylmethyl, (C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-ylmethyl, 2 - [(azetidine-3-carboxylic acid) -1- yl] ethyl, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] propyl , 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -propyl, (pyrrolidine-3-carboxylic acid) -1-yl-methyl, (C1-5-alkyl- pyrrolidine-3-carboxylic acid) -1-ylmethyl, (pyrrolidine-2-carboxylic acid) -1-ylmethyl, (C1-C5-alkyl-pyrrolidine-2-carboxylic acid ester) -1- ylmethyl, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5 pyrrolidin-3-carboxylic acid) -1-yl] ethyl ester, 2 - [(pyrrolidin-2-carboxylic acid) -1-yl] ethyl, 2 - [(C1-C5-alkyl-pyrrolidin-2-carboxylic acid) -1-yl] - ethyl, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] -propyl, 3 - [(C1,5-alkyl-pyrrolidin-3-carboxylic acid) -1-yl] -propyl ester, 3- [(pyrrolidin-2-carboxylic acid) -1-yl] -propyl, 3 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid) -1-yl] -propyl ester, -CH2- (CH2) n-COOH5-CH2- (CH2) n- CONR31R32j-CO-NHR31j- (CH2) nCH (OH) -CH2-NR31R32, C1-5 alkoxy fluoro-C1-5 alkoxy hydroxy, C2.5-alkoxy hydroxy, di - (hydroxy-C1-5-alkyl) -C1-5-alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH2- (CH2) m-NR R, 2-pyrrolidin-2-one 1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C1-5-alkyl) -piperazin-1-yl] -ethoxy, 2- [4- (2-Hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl-propoxy, 3- [4- (C1-5-alkyl) -piperazin-1-yl] -benzamide propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2 - [(azetidine acid -3-carboxylic) -1-yl] ethoxy, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [( pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 2 - [(C1-5-alkyl ester of pyrrolidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidine-2 -carboxylic) -1-yl] -ethoxy, 2 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid ester) -1-yl] -ethoxy, 2 - [(2-hydroxy-pyrrolidine) -1 -yl] -ethoxy, 2 - [(3-hydroxy-pyrrolidine) -1-yl] ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3 - [(C1-5- azetidine-3-carboxylic acid) -1-yl] propoxy alkyl ester, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] propoxy, 3 - [(C1-5-alkyl ester of pyrrolidin-3-carboxylic acid) -1-yl] propoxy, 3 - [(pyrrolidin-2-carboxylic acid) -1-yl] propoxy, 3 - [(C1-5-alkyl ester of pyrrolidine-2 - carboxylic) -1-yl] propoxy, 3 - [(2-hydroxy-pyrrolidine) -1-yl] propoxy, 3 - [(3-hydroxy-pyrrolidine) -1-yl] propoxy, 2-amino -3-hydroxy-2-hydroxymethylpropoxy, -O-CH2-CONR R, 3-carbamoylpropoxy, 3- (C1-5-alkylcarbamoyl) propoxy, 3- (2-hydroxyethylcarbamoyl) propoxy , -OCH2-CH (OH) -CH2-Nr3 1r325 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 2-hydroxy-3 - [(pyrrolidine-3-carboxylic acid) -1-ii] propoxy, 2-hydroxy-3 - [(C1-5-alkyl ester pyrrolidin-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(pyrrolidin-2-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C1-5 pyrrolidin-2-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(2-hydroxy-pyrrolidine) -1-yl] propoxy, 2-hydroxy-3 - [( 3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3- [4 - (C1-5-alkyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- morpholin-4-yl-propoxy, -NR31R32, -NHCO-R315-CH2- (CH2) k-NHSO2R335- (CH2) nCH (OH) -CH2-NHSO2R335-OCH2- (CH2) m-NHSO2R335 -0CH2-CH ( OH) -CH 2 -NHSO 2 R 33, -CH 2 - (CH 2) k -NHCOR 3 45 - (CH 2) n CH (OH) -CH 2 -NHCOR 34, -OCH 2 - (CH 2) m-NHCOR345 or -OCH2-CH (OH) -CH2-NHCOR34; R31 represents hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxy-ethyl, 2-hydroxy-1-hydroxy-methyl-ethyl, 2-C1-5-alkoxy-ethyl, 3-hydroxy-propyl, 3-C1-5-alkoxy-propyl, 2-amino-ethyl, 2- (C1-5-alkyl-amino) ethyl, 2- (di- (C1-5-alkyl) amino) ethyl, carboxy-methyl, C10 alkylcarboxymethyl, 2-carboxyethyl, or 2- (C1-5 alkylcarboxy) ethyl; R32 represents hydrogen, methyl, or ethyl; R33 represents methyl, ethyl, propyl, isopropyl, butyl, 2-hydroxyethyl, 2-methoxyethyl, methyl-amino, ethyl-amino, propyl-amino, isopropyl-amino, n-butyl-amino, or dimethyl-amino ; R34 represents hydroxymethyl, hydroxyethyl, aminomethyl, methylamino-methyl, dimethylamino-methyl, amino-ethyl, 2-methyl-amino-ethyl, or 2-dimethyl-amino-ethyl; k represents the integer 1, 2, or 3; m represents the integer 1 or 2; η represents O5 1, or 2; and R4 represents hydrogen, C1-6 alkyl, or halogen; and configurational isomers such as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts and solvent complexes of such compounds, and morphological forms. Compound according to claim 1, characterized in that R3 represents hydrogen, C1-5-hydroxy-alkyl, 2,3-dihydroxypropyl, di- (C1-5-hydroxy-C1-4 alkyl) 5-alkyl, -CH 2 - (CH 2) k-NR 31 R 32, (azetidine-3-carboxylic acid) -1-ylmethyl, (C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl methyl, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl-azetidine-3-carboxylic acid) -1-yl] ethyl ester, 3- [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -propyl, (pyrrolidine-3-acid carboxylic acid) -1-ylmethyl, (C1-5-alkylpyrrolidine-3-carboxylic acid ester) -1-ylmethyl (pyrrolidine-2-carboxylic acid) -1-ylmethyl Pyrrolidin-2-carboxylic acid-5-alkyl ester) -1-ylmethyl, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5 alkyl) pyrrolidine-3-carboxylic acid ester) -1-yl] ethyl, 2 - [(pyrrolidine-2-carboxylic acid) -1-yl] -e 2 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid) -1-yl] ethyl ester, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] propyl, 3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidine-2-carboxylic acid) -1-yl] -propyl, 3 - [(C1 Pyrrolidin-2-carboxylic acid-5-alkyl ester) -1-yl] propyl, -CH2- (CH2) n-CONR31R32, -CO-NHR315- (CH2) nCH (OH) -CH2-NR31R32, hydroxy C1-5-alkoxy, Auoro-C1-5-alkoxy, hydroxy-C2-5-alkoxy, C1-6 hydroxy-C1-6-alkyl-C1-6-alkoxy, 1-glyceryl, 2-glyceryl, -2-hydroxy-3 -methoxy-propoxy, -OCH2- (CH2) m-NR31 R32, 2-pyrrolidin-1-yl-ethoxy, -3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4 - (C1-5-alkyl) piperazin-1-yl] ethoxy, 2- [4- (2-hydroxyethyl) piperazin-1-yl] ethoxy, 3-piperazin-1-ylpropoxy , 3- [4- (C1-5-alkyl) -piperazin-1-yl] -propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4 -yl-ethoxy, 3-morpholin-4-yl-propoxy, 2 - [(azetidin-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(C1-5-alkyl azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 2 - [(C1-5 alkyl ester) pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-2-carboxylic acid) -1-yl] ethoxy, 2 - [(C1-5 alkyl ester of pyrrolidine-2 -carboxylic) -1-yl] ethoxy, 2 - [(2-hydroxy-pyrrolidine) -1-yl] -ethoxy, 2 - [(3-hydroxy-pyrrolidine) -1-yl] -ethoxy, 3 - [ (azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] propoxy, -3 - [(pyrrolidine acid -3-carboxylic) -1-yl] propoxy, 3 - [(C1-5-alkylpyrrolidine-3-carboxylic acid ester) -1-yl] propoxy, 3 - [(pyrrolidine-2-carboxylic acid ) -1-yl] propoxy, 3 - [(C1-5 alkyl-pyrrolidine-2-carboxylic acid ester) -1-yl] propoxy, 3 - [(2-hydroxy-pyrrolidine) -1-yl ] -propoxy, 3 - [(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxymethyl-propoxy, -O-CH2-CONR31R32, 3-carbamoyl-propoxy, 3 - (C1-5-alkylcarbamoyl) l) propoxy, -3- (2-hydroxy-ethylcarbamoyl) propoxy, -OCH 2 -CH (OH) -CH 2 -Nr 3 1 R 32,3 - [(azetidine-3-carboxylic acid) -1-yl] -2- hydroxypropoxy, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 2-hydroxy-3 - [(pyrrolidine-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl] -propoxy, 2-hydroxy-3 - [(pyrrolidine-acid) 2-carboxylic) -1-yl] propoxy, 2-hydroxy-3 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid ester) -1-yl] propoxy, 2-hydroxy-3- [ (2-hydroxypyrrolidin) -1-yl] propoxy, 2-hydroxy-3 - [(3-hydroxy-pyrrolidin) -1-yl] propoxy, -2-hydroxy-3-pyrrolidin-1-yl propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3- [4- (C1-5-alkyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4 - (2-hydroxyethyl) piperazin-1-yl] propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, -NR 1 R 3, -NHCO-R 31, -CH 2 - (CH 2) k -NHSO 2 R 33, - (CH 2) n CH (OH) -CH 2 -NHSO 2 R 33j-OCH 2 - (CH 2) m -NHSO 2 R 33, -0CH 2 -CH (OH) -CH 2 -NHS02R33, -CH2- (CH2) k -NHCOR34, - (CH2) nCH (OH) -CH2-NHCOR345-OCH2- (CH2) m-NHCOR34j or -OCH2-CH (OH) -CH2-NHCOR34 and in which R315 R325 R33 and R34 are as defined in claim 1. A compound according to claim 1 or 2, characterized in that the compounds represented in Formula (I) constitute the (1 R, 5aS) isomer of the 1,2-trimethyl-1, 1, 1, 5-derivative. , 5α-Tetrahydro-3-thia-cyclopropa [a] pentalene. A compound according to claim 1 or 2, characterized in that the compounds represented in Formula (I) constitute the (1S, 5aR) isomer of the 1,2-trimethyl-1, 1a, 5-derivative. , 5α-Tetrahydro-3-thia-cyclopropa [a] pentalene. A compound according to any one of claims 1 to 4, characterized in that the compounds represented in Formula (I) constitute a 5-thiophen-2-yl- [1,2,4] oxadiazole derivative. A compound according to any one of claims 1 to 4, characterized in that the compounds represented in Formula (I) constitute a 3-thiophen-2-yl- [1,2,4] oxadiazole derivative. A compound according to any one of claims 1 to 6, characterized in that R15 R2, and R4 represent hydrogen. A compound according to any one of claims 1 to 6, characterized in that R 1 represents hydrogen and R 2 and R 4 represent a methyl group. A compound according to any one of claims 1 to 6, characterized in that R 1 represents hydrogen, R 2 represents a methyl group and R 4 represents an ethyl group. A compound according to any one of claims 1 to 6, characterized in that R1 represents hydrogen, R2 represents a methoxy group and R4 represents chlorine. Compound according to any one of claims -1 and 3 to 10, characterized in that R represents hydrogen, C1-5-hydroxy-alkyl, 2,3-dihydroxy-propyl, di- (C1-hydroxy) -5-alkyl) -C1-5-alkyl, -CH2- (CH2) k-NR R, (azetidine-3-carboxylic acid) -1-ylmethyl, (C1-5-alkyl ester of azetidine acid) 3-carboxylic) -1-ylmethyl, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) - -1-yl] ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] propyl, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl ] -propyl, (pyrrolidine-3-carboxylic acid) -1-ylmethyl, (C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl-methyl, (pyrrolidine-2-carboxylic acid ) -1-ylmethyl, (C10-alkyl-pyrrolidin-2-carboxylic acid ester) -1-yl-methyl, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] -ethyl, 2- [(C1-5 alkyl-pyrrolidin-3-carboxylic acid) -1-yl] ethyl ester, 2 - [(pyrrolidinic acid α-2-carboxylic) -1-yl] ethyl, 2 - [{C1-5-alkyl-pyrrolidine-2-carboxylic acid) -1-yl] -ethyl ester, 3 - [(pyrrolidine-3 acid -carboxylic) -1-yl] -propyl, 3 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl] -propyl, 3 - [(pyrrolidine-2-carboxylic acid) - 1-yl] -propyl, 3 - [(C1-5-alkyl-pyrrolidin-2-carboxylic acid ester) -1-yl] -propyl, -CH2- (CH2) n-COOH, -CH2- (CH2) n-CONR31R32, -CO-NHR31, - (CH2) nCH (OH) -CH2-NR31R32, C1-5-alkoxy hydroxy, fluoro-C5-alkoxy, hydroxy-C2-5-alkoxy, di (C1-hydroxy) 5-alkyl) -C1-5-alkoxy, 1-glyceryl, 2-glyceryl, -2-hydroxy-3-methoxy-propoxy, -OCH2- (CH2) m-NR31R32, 2-pyrrolidin-1-yl-ethoxy, -3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C1-5-alkyl) -piperazin-1-yl] -ethoxy, 2- [4- ( 2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl-propoxy, 3- [4- (C1-5-alkyl) -piperazm-1-yl] -propoxy, 3- [4- (2-Hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2 - [(azetidine-3-ca carboxy) -1-yl] ethoxy, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidine-3-carboxylic acid) -1 -yl] ethoxy, 2 - [(C1-5-alkyl-pyrrolidine-3-carboxylic acid ester) -1-yl] -ethoxy, 2 - [(pyrrolidine-2-carboxylic acid) -l-yl] - 2 - [(C1-5 alkyl-pyrrolidin-2-carboxylic acid) -1-yl] ethoxy, 2 - [(2-hydroxy-pyrrolidine) -1-yl] -ethoxy, 2 - [ (3-hydroxypyrrolidine) -1-yl] ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(C 1-6 alkyl ester of azetidine-3-carboxylic acid ) -1-yl] propoxy, -3 - [(pyrimidin-3-carboxylic acid) -1-yl] propoxy, 3 - [(C10-alkyl-pyrrolidin-3-carboxylic acid ester) -1-yl ] -propoxy, 3 - [(pyrrolidine-2-carboxylic acid) -1-yl] -propoxy, 3 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid) -1-yl] -propoxy, 3 - [(2-hydroxy-pyrrolidine) -1-yl] -propoxy, 3 - [(3-hydroxy-pyrrolidine) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxymethyl-propoxy, -O-CH2-CONRjlRjz, 3-ca rbamoylpropoxy, 3- (C 1-6 alkylcarbamoyl) propoxy, -3- (2-hydroxyethylcarbamoyl) propoxy, -OCH 2 -CH (OH) -CH 2 -Nr 3 1 R 32,3 - [(azetidine-3 acid -carboxylic) -1-yl] -2-hydroxypropoxy, 3 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 2-hydroxy 3 - [(pyrrolidine-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C1-5 alkyl-pyrrolidine-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(pyrrolidine-2-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C1,5-alkyl-pyrrolidine-2-carboxylic acid ester) -1- yl] -propoxy, 2-hydroxy-3 - [(2-hydroxy-pyrrolidine) -1-yl] -propoxy, 2-hydroxy-3 - [(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2 -hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3- [4- (C1 -5-alkyl) -piperazin-1-yl ] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, or -NR R 5 - NHCO-R and wherein and R are as defined in claim 1 will. A compound according to any one of claims -1 to 10, characterized in that R represents hydroxy-C 2-5 alkoxy, di (hydroxy-C 1-5 alkyl) -C 1-5 alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2- (CH2) m-NR31 R32, 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl yl-ethoxy, 2- [4- (C1-5-alkyl) -piperazin-1-yl] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3- piperazin-1-yl-propoxy, 3- [4- (C1-5-alkyl) -piperazin-1-yl] -propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl]- propoxy, -2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2 - [(azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(C1-5- azetidine-3-carboxylic acid alkyl ester) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 2 - [(C1-5 alkyl ester of acid pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-2-carboxylic acid) -1-yl] ethoxy, 2 - [(C 1-5 alkylpyrrolidine-2-acid ester carboxylic) -1-yl] ethoxy, 2 - [(2- hydroxypyrrolidine) -1-yl] ethoxy, 2 - [(3-hydroxypyrrolidine) -1-yl] ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(C1-5 alkyl-azetidine-3-carboxylic acid) -1-yl] propoxy, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] propoxy, 3 - [(C6 pyrrolidin-3-carboxylic acid) -1-yl] propoxy, 3 - [(pyrrolidin-2-carboxylic acid) -1-yl] propoxy, 3 - [(C 1-6 alkyl ester) pyrrolidin-2-carboxylic acid) -1-yl] propoxy, 3 - [(2-hydroxy-pyrrolidin) -1-yl] -propoxy, 3 - [(3-hydroxy-pyrrolidin) -1-yl] -propoxy , 2-amino-3-hydroxy-2-hydroxymethyl propoxy, -O-CH 2 -CONR R 5 -3-carbamoyl propoxy, 3- (C1,5-alkylcarbamoyl) propoxy, 3- (2-hydroxy) ethylcarbamoyl) propoxy, -OCH 2 -CH (OH) -CH 2 -Nr 3 1 32, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy propoxy, 3 - [(C1-5 azetidine-3-carboxylic acid alkyl ester) -1-yl] -2-hydroxypropoxy, 2-hydroxy-3 - [(pyrrolidin-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy 3 - [(C1-5-alkyl est pyrrolidine-3-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(pyrrolidine-2-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(C1 (5-alkylpyrrolidine-2-carboxylic acid) -1-yl] propoxy, 2-hydroxy-3 - [(2-hydroxy-pyrrolidine) -1-yl] propoxy, 2-hydroxy-3-yl [(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-pin-olidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3-one [4- (C10-alkyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, or 2-hydroxy- 3-morpholin-4-yl-propoxy and wherein R31 and R32 are as defined in claim 1. Compound according to any one of claims - 3 to 10, characterized in that R3 represents hydroxy-C10-alkyl, -3-dihydroxy-propyl, di (hydroxy-C1.5-alkyl) -C1-5-alkyl, -CH2- (CH2) Ic-NR31R32, (azetidine-3-carboxylic acid) -1-ylmethyl, (C1-5-azetidine-3-carboxylic acid ester) -1 -yl-methyl, 2 - [(azetidine-3-carboxylic acid) -1-yl] -ethyl, 2 - [(C1-5-alkyl ester of azetidine-3-carboxylic acid) -l-yl] - ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(C1-5-alkyl-azetidine-3-carboxylic acid) -1-yl] -propyl acid ( pyrrolidine-3-carboxylic acid) -1-methylmethyl, (C1-5-alkyl ester of pyrrolidine-3-carboxylic acid) -1-ylmethyl (pinolidine-2-carboxylic acid) -1-ylmethyl , (C 1-5 alkylpyrrolidine-2-carboxylic acid ester) -1-ylmethyl, 2 - [(pyrrolidine-3-carboxylic acid) -1-yl] ethyl, 2 - [(C 1-5 pyrrolidine-3-carboxylic acid alkyl ester) -1-yl] ethyl, 2 - [(pyrrolidine-2-carbon acid pyrrolidine-2-carboxylic acid) -1-yl] ethyl, 2 - [(C1-5-alkyl-pyrrolidine-2-carboxylic acid ester) -1-yl] -ethyl, 3 - [(pyrrolidine-3-carboxylic acid) - 1-yl] -propyl, 3 - [(C1-5-alkyl-pyrrolidin-3-carboxylic acid ester) -1-yl] -propyl, 3 - [(pyrrolidin-2-carboxylic acid) -l-yl] -propyl, 3 - [(C1-5 alkyl-pyrrolidine-2-carboxylic acid) -1-yl] -propyl, -CH2- (CH2) n-COOH, -CH2- (CH2) n-CONR31R32 , -CO-NHR 31, or - (CH 2) n CH (OH) -CH 2 -NR 31 R 32 and wherein R 31 and R 32 are as defined in claim 1. A compound according to any one of claims 1 to 10, characterized in that R represents di- (hydroxy-C1-5-alkyl) -C1-5-alkoxy, 1-glyceryl, -OCH2- (CH2) m -NR 31 R 32, -O-CH 2 - CONR 31 R 32, or -OCH 2 -CH (OH) -CH 2 -Nr 31 R 32, wherein R 31 represents methyl or 2-hydroxyethyl and ether represents hydrogen. A compound according to any one of claims -1 and 3 to 10, characterized in that R represents -CH 2 - (CH 2) n -C00H, -CH 2 - (CH 2) n -CONR 31 R 32, -CH 2 - (CH 2) k-NHSO 2 R 33, - (CH 2) n CH (OH) -CH 2 -NHSO 2 R 33, -OCH 2 - (CH 2) m -NHSO 2 R 33, -OCH 2 -CH (OH) -CH 2 -NHSO 2 R 33, -CH 2 - (CH 2) k -NHCOR 34, - (CH2) nCH (OH) -CH2-NHCOR34, -OCH2- (CH2) m-NHCOR34, or -OCH2 -CH (OH) -CH2-NHCOR34 and wherein R31, R32, R33 and R34 are as defined in claim 1 . A compound according to claim 1, characterized in that it is selected from the group consisting of: -4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1 a, 5, 5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenol, -2- {4- [5 - (( laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4 ] oxadiazol-3-yl] -phenoxy} -ethanol, -1- (4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetramethyl) hydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol, (2 S) -3 - { 4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4- yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol, (2R) -3- {4- [5 - ((1 aS, 5 aR) -1 1,2-trimethyl-1,1a, 5,5α-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol, -1-methoxy-3- {4- [5 - ((1 aS, 5 aR) -1,1,2-trimethyl-1,1 a, 5,5a tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol , -2- {4- [5 - ((laS, 5aR) -1,1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentaen 4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy-methyl} -propane-1,3-diol, -3- {4- [5 - ((1 aS, 5aR) -1 1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-1-ol, dimethyl- (2- {4- [5 - ((laS, 5aR) -1,1,2-trimethyl-1,1α, 5,5a-tetrahydro-3 -thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -amine, dimethyl- (2- {4- [5- ( (1S, 5aR) -1,1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2, 4] oxadiazol-3-yl] -phenoxy} -ethyl) -amine, -2,6-dimethyl-4- [5 - ((1 aS, 5 aR) -1,1,2-trimethyl-1,1 a , 5,5a-Tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenol, -2- {2,6- dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4- yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -ethanol, -1- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2 -trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen -4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol, (2S) -3- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol, (2R) -3- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2- trimethyl-1,1α-Satranyl-S-thia-cycloproppropylpentenyl-1 H-yl-propane-1,2-diol, -1- {2,6-dimethyl-4- [5 - (( 1 aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4 ] oxadiazol-3-yl] -phenoxy} -3-methoxy-propan-2-ol, -2- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,1,2-trimethyl -1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy-methyl} -acetamide propane-1,3-diol, -3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetramethyl) hydro-3-thi-cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propan-1-ol, (2- {2,6 -dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl ) - [1,2,4] oxadiazol-3-yl] phenoxy} ethyl) di methylamine, -3- [3,5-dimethyl-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5 - ((1 aS, 5aR) -1,1,2-trimethyl 1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazole, -4- (2- {2,6-one dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4 -yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -morpholine, -3- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1 1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl-amine, (3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetramethyl) hydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -methyl-amine, (3- {2,6 -dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4 -yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -dimethyl-amine, -2- (3- {2,6-dimethyl-4- [5 - ((1 aS , 5aR) -1,1,2-trimethyl-1,1α, 5,5α-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazole -3-yl] -phenoxy} -propyl-amino) -ethan ol, -3 - [3,5-dimethyl-4- (3-pyrrolidin-1-yl-propoxy) -phenyl] -5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1 a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazole, (3- {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,2,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1, 2,4] oxadiazol-3-yl] -phenoxy} -propyl) -propyl-amine, -2- (3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,1, 2-trimethyl-1,1α, 5,5-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} - propylamino) propane-1,3-diol, N1 - (3- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl-1,1 tetrahydro-S-thia-cyclopropa [a] pentalen propyl) -ethane-1,2-diamine, 1- (3- {2,6-dimethyl-4- [5 - ((laS, 5aR) acid -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3 yl] -phenoxy} -propyl) -pyrrolidine-2-carboxylic acid 1- (3- {2,6-dimethyl-4- [5 - ((laS, 5aR) -1,2,2-trimethyl-1 , 1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] phenoxy} -propyl) -pyrroli dine-3-carboxylic, -2- [4- (3- {2,6-dimethyl-4- [5 - ((1 aS, 5 aR) -1,1,2-trimethyl-1,1 a, 5 , 5 α-Tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -piperazin-1-yl ] -ethanol, -2-amino-2- {2,6-dimethyl-4- [5 - ((1 aS, 5aR) -1,1,2-trimethyl--1,1 a, 5,5a-tetra -hydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy-methyl} -propane-1,3-diol, (3 - {2,6-dimethyl-4- [5 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -isopropyl-amine, (3- {2,6-dimethyl-4- [5 - ( (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclo-propa [a] pentalen-4-yl) - [1,2, 4] oxadiazol-3-yl] -phenoxy} -propyl) - (2-ethoxy-ethyl) -amine, -2,6-dimethyl-4- [3 - ((1 aS, 5aR) -1,2,2 -trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenol, - 2- [2,6-dimethyl-4- [3 - ((laS, 5aR) -1,2,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclopropa [ a] pentalen-4-yl) - [1, 2,4] oxadiazol-5-yl] -phenoxy} -ethanol, -1- [2,6-dimethyl-4 [3 - ((1 aS, 5 aR) -1,1,2-trimethyl-1,1 α, 5.5 α-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenoxy} -propan-2-ol -3- [2,6-dimethyl-4- [3 - ((laS, 5aR) -1,1,2-trimethyl-1,1α, 5,5a-tetrahydro-3-thia-cyclohexane propa [a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenoxy} -propane-1,2-diol, -3 - [2,6-dimethyl-4- [3 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [ 1,2,4] oxadiazol-5-yl] -phenoxy} -propane-1,2-diol, -2- [2,6-dimethyl-4- [3 - ((1 aS, 5 aR) -1, 1,2-trimethyl-1,1α, 5,5-α-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1,2,4] oxadiazol-5-yl] -phenoxy-methyl} -propane-1,3-diol, and -3- (3-trifluoromethyl-phenyl) -5 - ((laS, 5aR) -1,2,2-trimethyl--1, la, 5, 5α-tetrahydro-3-thia-cyclopropa [Î ±] pentalen-4-yl) - [1,2,4] oxadiazole.